TW201309639A - Oxime derivatives as GPR119 agonists - Google Patents

Abstract

The present invention relates to oxime derivatives of Formula 1, a method for preparing the same, a pharmaceutical composition comprising the same and use thereof. The oxime derivatives according to the present invention act as GPR119 agonists to stimulate the secretion of insulin and promote GLP-1 formation for preventing or treating type 2 diabetes, complications of diabetes, obesity, dyslipidemia or osteoporosis. wherein, RA, RB, n, Ar, A, B, R1 and R2 are as defined herein.

Description

Anthracene derivative as GPR119 agonist

The present invention relates to a novel indole derivative as a GPR119 agonist, a process for the preparation thereof, a pharmaceutical composition containing the same, and the use of the derivative. Herein, the GPR119 agonist refers to a compound which can be effectively used for preventing or treating diabetes, diabetic complications, obesity, dyslipidemia or osteoporosis by stimulating the pancreas to secrete insulin and promoting the formation of GLP-1 and GIP in the gastrointestinal tract. .

Diabetes is divided into two types - insulin dependent type 1 diabetes and non-insulin dependent (insulin resistant) type 2 diabetes that occurs in 90% or more of diabetic patients.

In insulin-resistant type 2 diabetic patients, endogenous insulin is not fully effective, so blood sugar is required to be controlled in another way, and oral hypoglycemic agents are most commonly used.

Currently, most anti-diabetic agents control the action of blood sugar to affect one of the target organs, such as the liver, pancreas or muscle. For example, sulfonylureas act directly on the pancreas, allowing them to secrete insulin, while the action of metformin prevents the glycolytic action of the liver. However, in many cases it is difficult to achieve the desired effect with a single drug, and each drug has side effects. The problem with sulfonylureas is that they reduce pancreatic function and cause hypoglycemia due to excessive secretion of insulin, while metformin causes gastrointestinal or nephrotoxicity. Glitazone also causes side effects such as weight gain, severe heart failure, and the like. At the same time, the recently released enteroprotein (Incretin) related drugs (such as: DPPIV inhibitors or Exenatide) have become a solution to the problems that traditional antidiabetic agents cannot solve (eg, increased glucagin production, β-cells in the pancreas) An important medicine that gradually declines in function, causes hypoglycemia, increases body weight, and so on. However, the efficacy of DPPIV inhibitors is limited, and there are reports specifically mentioning the side effects of high saccharide infusion (Galvus) with dermal toxicity. In addition, a disadvantage of the glycosaminoglycan is that it must be administered by injection.

As described above, most antidiabetic agents have various problems and side effects, and therefore it is highly desirable to develop a new anti-diabetic agent which can be used to effectively and safely treat diabetes.

The known anti-diabetic potency of GPRl 19 agonists that may have been used to treat type 2 diabetes is that (1) stimulates the pancreas to secrete insulin, and (2) increases intestinal hormones in the intestinal cells.

Therefore, the GPR119 agonist exhibits anti-diabetic efficacy by directly acting on β-cells in the pancreas to stimulate GSIS and acting on intestinal cells to stimulate secretion of the gut hormones GLP-1, GIP and PYY. It is known that GLP-1 acts on β-cells in the pancreas and stimulates the secretion of insulin. It also has various anti-diabetic and anti-obesity effects, and prevents and treats osteoporosis, including reducing postprandial glucagon secretion and lowering the gastrointestinal tract. It has activity, reduces appetite, reduces body weight and proliferates β-cells in the pancreas. Therefore, the GPR119 agonist that stimulates the secretion of the secretin hormone should also have the efficacy of an enterin hormone.

Based on the above description, research on the PR119 agonist is actively underway. Among the representative compounds that can act as GPR119 agonists, the claimed patents are mainly based on the attachment of the left and right substituents and determine the entire structure. The center of the orientation is bridged. GPR119 agonist compounds having an aromatic substituent have been disclosed in WO2007/003964, WO2008/109702, WO2008/076243 and WO 2008/085316.

It is an object of the present invention to provide an anthracene derivative which is a GPR119 agonist.

Another object of the present invention is to provide a process for preparing the anthracene derivative.

Another object of the present invention is to provide a pharmaceutical composition for preventing and treating diabetes, diabetic complications, obesity, dyslipidemia or osteoporosis, comprising an anthraquinone derivative as an active ingredient, and providing a method for preparing the composition .

Another object of the present invention is to provide a method for preventing and treating diabetes, diabetic complications, obesity, dyslipidemia or osteoporosis, which uses an anthracene derivative as an active ingredient.

Accordingly, the present invention provides an anthracene derivative of the formula I, or a pharmaceutically acceptable salt thereof or an isomer thereof:

Wherein RA represents a partially or fully saturated 4- to 7-membered cycloalkyl group, RB represents a partially or fully saturated 4- to 7-membered heterocyclic ring, or consists of two rings [5.5], [5.6] ], [5.7], [6.6] or [6.7] fused ring system, R1 and R2 each independently represent hydrogen, halogen or alkyl, wherein n represents an integer from 0 to 10, and A represents nitrogen or carbon, B system Selected from the following groups:

Wherein D represents carbon, nitrogen, oxygen or sulfur, and R3, R4 and R5 are each independently hydrogen or halogen, or respectively represent an aryl group, an arylalkyl group, an alkyl group, a cycloalkyl group or a cycloalkyl group which may be optionally substituted. An alkyl group, a heterocyclic group, a heterocyclic alkyl group or an amine, but the limitation is that when D is oxygen or sulfur, neither R3 nor R4 is present, and when D is sulfur, R5 is not an amine, when D In the case of nitrogen, R3 is absent. When D is carbon, two groups selected from R3, R4 and R5 are joined together to form a 3- to 7-membered cycloalkyl or heterocyclic ring which may optionally be substituted, or formed. A 5- or 6-membered aryl or heteroaryl group may be optionally substituted, and E, F, G, H and I each independently represent carbon, nitrogen, oxygen or sulfur to form a 6-membered aryl or heteroaryl group, Or forming a benzo-fused 5-membered aryl or heteroaryl group excluding one of E, F, G, H and I, n represents an integer from 0 to 5, and R6 is hydrogen. Or halogen; or an alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl or heteroarylalkyl group optionally substituted; or a hydroxy group or optionally 1 or 2 alkyl groups or An aryl substituted amine wherein the two substituents of the amine Co-ligated to form a 3- to 7-membered heterocyclic group, J represents a C ₁ -C ₄ -alkyl or sulfonyl group which may be substituted, R 7 is hydrogen or halogen, or represents an alkyl group which may be substituted as desired A cycloalkyl, aryl, heteroaryl or heterocyclic group, and Ar represents an aryl or heteroaryl group which may be optionally substituted.

The compound of formula 1 according to the present invention may form a pharmaceutically acceptable salt thereof, which includes inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid; organic acids such as tartaric acid, formic acid, Citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicylic acid; or sulfonic acid, such as: methanesulfonic acid, ethanesulfonic acid, benzenesulfonate An addition salt of an acid and p-toluenesulfonic acid which forms a non-toxic acid addition salt comprising a pharmaceutically acceptable anion. For example, pharmaceutically acceptable carboxylates include salts with alkali or alkaline earth metals (eg, lithium, sodium, potassium, calcium, and magnesium); and amino acids (eg, lysine, arginine, and胍) formed salts; organic salts such as dicyclohexylamine, N-methyl-D-glucosamine, cis (hydroxymethyl)methylamine, diethanolamine, choline and triethylamine. The compound of the formula 1 according to the present invention can be converted into its salt by a conventional method.

Furthermore, since the compound of formula 1 according to the invention may have an asymmetric carbon center and an asymmetric axis or plane, it may be an E- or Z-isomer, an R- or S-isomer, a racemic mixture or a non-pair Mixtures and their respective diastereomers, and the like, are intended to be encompassed within the scope of the invention.

As used herein, unless otherwise indicated, the term "compound of formula 1" refers to all compounds of formula 1, including pharmaceutically acceptable salts thereof and isomers thereof.

The terms used herein are defined as follows.

Halogen or halo means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Alkyl means a straight or branched hydrocarbon which may contain a single bond, a double bond or a reference bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethynyl, vinyl, trifluoromethyl, and the like. Group.

Cycloalkyl means a partially or fully saturated monocyclic or fused cyclic hydrocarbon and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like. Group.

Aryl means aromatic hydrocarbons and includes, but is not limited to, phenyl, naphthyl, and the like.

Heteroaryl means an aromatic hydrocarbon which forms a monocyclic or fused ring and which contains at least one hetero atom selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, indole base, Diazolyl, different Diazolyl, tetrazolyl, triazolyl, fluorenyl, iso Azolyl, Azolyl, thiazolyl, imidazolyl, thienyl, benzothiazole, benzimidazole, 1,2,3,4-tetrahydroisoquinolinyl, thiazolopyridinyl, and the like.

Heterocyclic group means a partially or fully saturated hydrocarbon which forms a monocyclic or fused ring and which contains at least one hetero atom selected from N, O and S. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperidine Base, tetrahydrofuran, tetrahydrothiofuran, and the like.

The arylalkyl group and the heteroarylalkyl group mean a group formed by combining the above aryl group with an alkyl group and a combination of a heteroaryl group and an alkyl group. Examples thereof include, but are not limited to, benzyl, thiophenemethyl, pyrimidinemethyl, and the like.

The above amine, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl and heteroarylalkyl groups may be substituted with at least one group selected from the group consisting of alkyl groups, rings Alkyl, heterocyclic, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, pendant oxy, cyano, halo, nitro, -OR, -OC ( O) R, -OC(O)OR, SR, -S(O)R, -S(O) ₂ R, -C(O)R, -C(O)OR, -C(S)R, - C(O)NRR, -NR ₂ , -NRCHO, -NRC(O)R, -NRC(O)NRR, -C(S)NRR, -NRC(S)R, -NRC(S)NRR, where R Individually selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, and when two R are substituted, they may be joined to form a ring. Alkyl or heterocyclic group.

Preferred compounds of the formula 1 according to the invention which can be used as GPR119 agonists are those in which A is nitrogen.

Other preferred compounds are those wherein B is selected from the group consisting of:

Wherein n, R3, R4, R5, R6 and R7 are as defined above.

Other preferred compounds are those wherein Ar represents a compound of the formula:

Wherein, K, L, M, Q and T each independently represent carbon or nitrogen and form a phenyl or 6-membered heteroaryl group, or when one of K, L, M, Q and T does not exist, represents 5 a heteroaryl group in which an oxygen, nitrogen or sulfur may be added as a ring atom, n represents an integer from 1 to 5, and R8 is independently hydrogen, halogen, cyano or nitro, respectively, or an alkane which may optionally be substituted, respectively. a group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amine group, a hydroxyl group, an ethynyl group or a vinyl group, or is selected from the group consisting of:

Among them, U is selected from the group consisting of carbon, nitrogen, oxygen, phosphorus and sulfur. When U is sulfur or phosphorus, n stands for 1 or 2 respectively. When U is carbon or nitrogen, n stands for 1, when U is oxygen. , n represents 0, R9 represents hydrogen or may be substituted with a hydroxyl group, an amine, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and V represents carbon, nitrogen, oxygen or sulfur.

R10, R11 and R12 are each independently hydrogen, halogen or aminemethanyl, or represent a hydroxy, alkyl, amine, cycloalkyl, heterocyclyl, aryl or heteroaryl group which may optionally be substituted, or selected from R10. Two of R11 and R12 may be bonded to form one ring, and when V is oxygen or sulfur, R11 is not present.

Particularly preferred compounds are those in which the Ar is selected from the group consisting of:

Wherein n represents an integer from 1 to 5, R8 is a nitro group, or represents a hydroxy, alkyl, ethynyl, amine, heteroaryl or heterocyclic group which may be optionally substituted, or is selected from the group consisting of:

Wherein n, R9, R10, R11 and R12 are as defined above.

The compounds of the formula 1 according to the invention are those in which the RA is selected from the group consisting of:

RB is selected from the following groups:

Wherein R 1 and R 2 each independently represent hydrogen or C ₁ -C ₆ -alkyl, wherein n in each ring represents an integer from 0 to 9, A represents nitrogen, and B is selected from the group consisting of:

Wherein, n represents an integer of 0 to 5, and R3, R4 and R5 are each independently hydrogen or halogen, or represent C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ - ring Alkyl-C ₁ -C ₆ -alkyl, C ₅ -C ₁₀ -aryl, C ₅ -C ₁₀ -aryl-C ₁ -C ₆ -alkyl, heterocyclyl or heterocyclyl-C ₁ - a C ₆ -alkyl group (wherein the heterocyclic group is a moiety comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as a ring atom or fully saturated 3- to 10-membered); or R 4 is bonded to R 5 to form C _{a 3-} C ₁₀ -cycloalkyl group, or a hetero atom containing from 1 to 3 selected from nitrogen, oxygen and sulfur as a part of a ring atom or a fully saturated 3- to 10-membered ring; wherein R3, R4 and R5 are defined In the above, each group may be substituted with at least one group selected from the group consisting of halogen, hydroxyl, amine, pendant oxy, carboxyl, C ₁ -C ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkyl, and R 6 represents hydrogen. , halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₃ -C ₁₀ -cycloalkyl, C ₁ -C ₆ -alkoxy, C ₅ -C ₁₀ -aryl Or a di(C ₁ -C ₆ -alkyl)amine, and n represents 0 or 1, R 7 is hydrogen or halogen, or represents C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₅ -C ₁₀ -aryl, or including 1 to 3 a hetero atom of nitrogen, oxygen and sulfur as a 5- or 6-membered heteroaryl group of a ring atom, wherein each group in the definition of R7 may be optionally substituted with at least one group selected from the group consisting of halogen, hydroxy, amine, side oxygen. a group, a carboxyl group, a C ₁ -C ₆ -alkoxycarbonyl group and a C ₁ -C ₆ -alkyl group, the Ar system being selected from the group consisting of:

Wherein n represents 1 or 2, R8 is nitro or hydroxy-C ₁ -C ₆ -alkyl, or an amine which may be 1- or 2-substituted by a C ₁ -C ₆ -alkylsulfonyl group, if desired, a part or fully saturated 5- or 6-membered heterocyclic group including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted by a pendant oxy group, or 1 to 4 selected from nitrogen and oxygen And a hetero atom of sulfur as a 5- or 6-membered heteroaryl group of the ring atom, or is selected from the group consisting of:

Wherein n represents 1 or 2, and R9 represents an amine group, a hydroxyl group, a C ₁ -C ₆ -alkyl group, a C ₁ -C ₆ -alkoxy group, a C ₃ -C ₁₀ -cycloalkyl group, a C ₃ -C ₁₀ - Cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylamine, bis(C ₁ -C ₆ -alkyl)amine, C ₃ -C ₁₀ -cycloalkylamine, C ₅ - a C ₁₀ -arylamine, a C ₅ -C ₁₀ -aryl-C ₁ -C ₆ -alkylamine, a heterocyclic group or a heterocyclic-C ₁ -C ₆ -alkylamine (wherein the heterocyclic group includes 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as part of a ring atom or fully saturated 3- to 10-membered ring), wherein each group in the definition of R9 may optionally have at least one group selected from the group consisting of Substituting: halogen, hydroxy, amine, pendant oxy, carboxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxycarbonyl, aminecarboxamyl and C ₁ -C ₆ -alkyl, and R10, R11 and R12 each independently represent hydrogen, hydroxy, halogen, aminemethanyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, hydroxy-C ₁ -C ₆ -alkyl, C _1- C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₅ -C ₁₀ -aryl, C ₁ -C ₆ -alkylamine, di(C ₁ -C ₆ -alkyl)amine , C ₃ -C ₁₀ -cycloalkylamine, C ₅ -C ₁₀ -arylamine or C ₅ -C ₁₀ -aryl-C ₁ -C ₆ -alkylamine, or a heterocyclic group or a heterocyclic group -C ₁ -C ₆ -alkyl,heterocyclyl-C ₁ -C ₆ -alkylamine (wherein the heterocyclic group is a part of a ring atom comprising from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur Or fully saturated 3- to 10-membered ring) or heteroarylalkyl (wherein the heteroaryl group includes 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as part of the ring atom or fully saturated 3- to a 4-membered aromatic ring); or two groups selected from the group consisting of R10, R11 and R12 are bonded to form a C ₃ -C ₁₀ -cycloalkyl group, including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring a 4- to 6-membered heteroaryl group of an atom, or a hetero atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom or a fully saturated 4- to 6-membered heterocyclic group, wherein R10, Each of the groups defined by R11 and R12 may be optionally substituted with at least one group selected from the group consisting of halogen, hydroxy, amine, pendant oxy, carboxy, azide, C ₃ -C ₁₀ -cycloalkyl, C ₁ - C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyloxy and C ₁ -C ₆ -alkyl.

Representative compounds of formula 1 according to the invention include, but are not limited to, the following compounds: 4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidin-1-carbonyl) -amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester; 4-(4-{2,5-difluoro-4-[(3- Hydroxy-azetidine-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 3-hydroxy-azetidine Alken-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl} -phenyl)-guanamine; 3-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2, 5-difluoro-phenyl)-1,1-dimethyl-urea; 3-hydroxy-azetidin-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidine-) 2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-guanamine; 4-cyclopropyl-piperidyl 1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-guanamine; (4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl --urea; 4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester; 4 -[4-(2,5-Difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester; 4-[4-(2 ,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester; (2,5-difluoro-4-{ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 3-(2,5-difluoro- 4-{4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea 4-[4-(2,5-Difluoro-4-{[(3-hydroxy-azetidin-1-carbonyl)-amino]-methyl}-phenyl)-cyclohexyleneamine Isopropyl]-piperidine-1-carboxylic acid isopropyl ester; 4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexyleneaminooxy]-piperidine 1-carboxylic acid isopropyl ester; 4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexyleneaminooxy}-peripipeline 1-carboxylic acid isopropyl ester; 4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexyleneaminooxy}-peripipeline Isopropyl 1-carboxylic acid; 4-(4-{2,5-difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexyleneamine Isopropyl)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{4-[3-(2,3-dihydroxy-propyl)-ureido]-2,5-difluoro -phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-[4-(4-methanesulfonyl-phenyl)-cyclohexylideneaminooxy ]-piperidine-1-carboxylic acid tert-butyl ester; 4-(4-{4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclo ring Benzylaminooxy)-piperidine-1-carboxylic acid tert-butyl ester; 4-(4-{4-[(3-hydroxy-azetidin-1-yl)-amino]-benzene }}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5- Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 3-hydroxy-azetidin-1-carboxylic acid (2, 5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(2,5-difluoro-4-{4-[1-( 3-isopropyl-[1,2,4] (oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea; (2,5-difluoro-4 -{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5 -methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)- Urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4-yloxyimino]-cyclohexyl}-benzene 3-(2-hydroxy-propyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine- 4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5 -methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea; 1-(2,5 -difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2- Hydroxy-1-hydroxymethyl-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4- Methoxyimido]-cyclohexyl}-phenyl)-3-(2,3-dihydroxy-propyl)-urea; N-(2,5-difluoro-4-{4-[1-( 5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide; 1-(3-fluoro-4-{4-[ 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2- (3-ethyl-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4 ] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2,5- Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea; N-(2,5- Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Oxazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide; {2,5-difluoro-4-[4-(1-thiazole) -2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-urea; {2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidyl) Methyl pyridin-4-yloxyimino)-cyclohexyl]-phenyl}-aminecarboxylate; {4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxy) Amino)-cyclohexyl]-2,5-difluoro-phenyl}-urea; {4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxyimino)- Cyclohexyl]-2,5-difluoro-phenyl}-aminocarboxylic acid methyl ester; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4- Methoxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(4-{4-[1-(5-B -Pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea; -(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)- 3-(3-hydroxy-2,2-dimethyl-propyl)-urea; 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2 , 4] Azoxa-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea; 2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 3-hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxy) Imino]-cyclohexyl}-phenyl)-guanamine; butane-1-sulfonic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidine-4- 4-[4-(2,5-difluoro-4-indolylcarbonyl-phenyl)-cyclohexane Benzylaminooxy]-piperidine-1-carboxylic acid tert-butyl ester; (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy) Amino]-cyclohexyl}-2,5-difluoro-phenyl)-urea; (R)-3-fluoro-pyrrolidine-1-carboxylic acid (4-{4-[1-(5-ethyl) -pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-decylamine; (4-{4-[1-(5- Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea; (4-{4-[1-(5-chloro-) Pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea; 1-(4-{4-[1-(5- Chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]- Hexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea; 3-hydroxy-azetidine-1-carboxylic acid {2,5-difluoro-4 -[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yloxyimino)-cyclohexyl]-phenyl }-decylamine; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-di Fluoro-phenyl)-3-(2-hydroxy-propyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy Imino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4- [1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea ; 1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl) 3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine- 4-yloxyimino]-cyclohexyl}-phenyl)-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea; {2,5-difluoro-4-[4 -(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yloxyimino)-cyclohexyl]-phenyl}-urea (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl }-phenyl)-urea; (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl }-phenyl)-urea; 1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino] -cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 3-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4- Methoxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea; 3-(2,5-difluoro-4-{4-[1- (3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea; 3-(2,6-difluoro-4- {4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea; -(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)- 3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea; 1-(2,5-difluoro-4-{4-[ 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea; 1-(2,5-di Fluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy- Propyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-per Pyridin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidine-2- -(piperidin-4-yloxyimino)-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(2,6-difluoro-4-{4 -[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3 -(3-hydroxy-propyl)-urea; 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxy Imino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 4-[4-(2-fluoro-4-ureido-phenyl)-cyclohexyleneamino Oxy]-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{2-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclo ring Hexylaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2-fluoro-benzene }}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]- 2,5-difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; (4-{4-[1-(5-cyclopropyl-pyrimidine- 2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea; 1-(4-{4-[1-(5-cyclopropane) -Pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea; 2,5-difluoro-4-{4-[4-(3-isopropyl-[1,2,4] (oxazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea; (2,5-difluoro-4-{4-[4-(3-isopropyl-[ 1,2,4] (oxazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea; (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidine- 2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-dicarbodiimide-diearbonimidic diamide; 1-(2,5-difluoro-4- {4-[1-(5-Fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxy) Imino]-cyclohexyl}-phenyl)-guanamine; 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidine-4 -yloxyimido]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-( 5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea; 1-(2,5-difluoro-4 -{4-[1-(5-Fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)- Urea; 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl (3-thiophen-2-ylmethyl-urea; (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino) ]-cyclohexyl}-phenyl)-urea; (2,3-difluoro- 4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 3-hydroxy-nitrogen heterocycle Butane-1-carboxylic acid (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl }-phenyl)-guanamine; 1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino) ]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea; 1-(2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl) -piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (2 -fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine; 1-( 4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3- (3-hydroxy-propyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidine- 4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-decylamine; (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidyl) Pyridin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl) )-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-benzene --3-(2-hydroxy-propyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino] -cyclohexyl}-2,3-difluoro-phenyl)-3-propyl-urea 4-[4-(3-fluoro-4-ureido-phenyl)-cyclohexyleneaminooxy]- Piperidine-1-carboxylic acid isopropyl ester; (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxy) Imino]-cyclohexyl}-phenyl)-urea; (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclo Hexyl}-2-fluoro-phenyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclo Hexyl}-2-fluoro-phenyl)-3-(3-hydroxy-propyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidine 4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydroxy-propyl)-urea; 3-hydroxy-azetidine-1-carboxylic acid ( 4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-decylamine; 4- Ethyl methyl 2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylate; 4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid (2 -fluoro-ethyl)-guanamine; 4-(5-hydroxymethyl-4- Methyl-thiazol-2-yl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole; 3-hydroxy-azetidine 1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl }-phenyl)-guanamine; 4-(4-{3-fluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexyleneamine Isopropyl)-piperidine-1-carboxylic acid isopropyl ester; 1-(2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)- Piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 3-hydroxy-azetidine-1-carboxylic acid (2, 5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine ;[(S)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-(4-{4-[1-(5-methyl-pyrimidin-2-yl)-per Butyl-4-yloxyimino]-cyclohexyl}-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester; 4-{4-[(S)-2- Amino-3-((S)-3-fluoro-pyrrolidin-1-yl)-3-oxo-propyl]-phenyl}-cyclohexanone O-[1-(5-methyl- Pyrimidin-2-yl)-piperidin-4-yl]-indole; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimine Base]-cyclohexyl}-2,5-difluoro-phenyl)-3-methyl- ; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl --3-propyl-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2 ,5-difluoro-phenyl)-3-isopropyl-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidyl Pyridin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea; 4-[4-(2-fluoro-4-phenoxycarbonylamino-phenyl)- Phenylcyclohexylideneoxy]-piperidine-1-carboxylate; 4-[4-(3-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy - piperidine-1-carboxylic acid phenyl ester; 4-[4-(2,5-difluoro-4-phenoxycarbonylamino-phenyl)-cyclohexyleneaminooxy]-piperidine 1-carboxylic acid phenyl ester; 4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexyleneaminooxy}-piperidine- 1-carboxylic acid phenyl ester; 4-{4-[4-(3,3-dimethyl-ureido)-2,5-difluoro-phenyl]-cyclohexyleneaminooxy}-peripipeline Phenyl-1-carboxylic acid phenyl ester; 4-(4-{2,5-difluoro-4-[(3-hydroxy-azetidin-1-yl)-amino]-phenyl}- Phenylcyclohexylamidooxy)-piperidine-1-carboxylate; 4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]- Phenylcyclohexylideneoxy}-piperidine-1-carboxylate; 3-hydroxy-azetidin-1-carboxylic acid (2,5-difluoro-4-{4-[(Z) --1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohex-1-enyl}-phenyl)-guanamine; 4-{4- [3-Fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-{4-[2-fluoro 4-(2-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-(4-{3-fluoro-4-[ 3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 4-(4-{2-fluoro-4 -[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 4-{4-[4-( 3,3-Dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-(4-{3-fluoro- 4-[3-(2-Fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 3-(2-fluoro-4 -{4-[1-(3,3,3-Trifluoro-propyl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea 3-{4-[4-(1-Benzyl-piperidin-4-yloxyimino)-cyclohexyl]-2-fluoro-phenyl}-1,1-dimethyl-urea; 3-{2-fluoro-4-[4-(1- Naphthalen-2-ylmethyl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-1,1-dimethyl-urea; 4-(4-{3-fluoro-4- [(3-Hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 4-(4- {3-Fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4- (4-{3-Fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester 3-{4-[2-Fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-pyrrolidine-1-carboxylic acid phenyl ester; 4-( 4-{3-Fluoro-4-[3-(2-hydroxy-1-methyl-ethyl)-ureido]-phenyl}-cyclohexylideneamino)-piperidine-1-carboxylic acid Isopropyl ester; 4-(4-{3-fluoro-4-[3-(2-hydroxy-propyl)-ureido]-phenyl}-cyclohexyleneaminooxy)-piperidine-1 -isopropyl carboxylic acid; 4-(4-{3-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexyleneaminooxy)-peripipeline Isopropyl 1-carboxylic acid; 4-{4-[3-fluoro-4-(3-methyl-ureido)-phenyl]-cyclohexyleneamino}-piperidin-1 -isopropyl carboxylic acid; 4-{4-[3-fluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexyleneamino oxygen }-piperidine-1-carboxylic acid isopropyl ester; 4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexyleneaminooxy }-piperidinyl-isopropyl isopropyl ester; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclo Hexyl}-2-fluoro-phenyl)-methyl-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino) ]-cyclohexyl}-2-fluoro-phenyl)-3-(2-hydro-1-methyl-ethyl)-urea; 4-{4-[3-fluoro-4-(3-propyl- Ureido)-phenyl]-cyclohexylideneaminooxy}-piperidinyl-carboxylic acid isopropyl ester; 4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl) -3-methyl-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 1-(2-fluoro-4-{4-[1 -(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea; 3-(2-fluoro-4-{4-[1- (3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea; 1-(2-fluoro-4-{4- [1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2-fluoro- 4-{4-[1-(3-isopropyl-[1,2,4] (oxazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea; (2-fluoro-4-{4-[1-( 3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 1-(2-fluoro-4-{4-[1-(3-isopropyl) Base-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea; 1-(2 -fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 1-(2-fluoro-4- {4-[1-(3-isopropyl-[1,2,4] Oxazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea; 3-hydroxy-azetidin-1-carboxylic acid ( 2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(2-fluoro-4-{4-[1-(3-iso) Propyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea; 1-(2,5-difluoro 4-{4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((R)-2 -hydroxy-1-methyl-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4- Methoxyimino]-cyclohexyl}-phenyl)-3-((S)-2-hydroxy-1-methyl-ethyl)-urea; 4-[4-(2,5-difluoro- 3-ureido-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; 4-(2,5-difluoro-4-tetrazole-1- -Phenyl)-cyclohexenone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole; 4-p-tolyl-cyclohexanone O-[ 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole; 4-naphthalen-2-yl-cyclohexanone O-[1-(5-methyl-pyrimidine-2 -yl)-piperidin-4-yl]-indole; 3-hydroxy-azetidin-1-carboxylic acid (3-methyl-4-{4-[1-(5-methyl-pyrimidine-) 2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 3-hydroxy-azetidin-1-carboxylic acid (3-methoxy-4) -{4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine; 1-(6-{4 -[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxy Amino]-cyclohexyl}-pyrimidin-3-yl)-3-propyl-urea; and 3-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy] -8-Aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester.

The terms and abbreviations used herein have their original definitions unless otherwise indicated herein.

The invention also provides a process for the preparation of a compound of formula 1. Hereinafter, the method of preparing the compound of Formula 1 illustrates the present invention based on the exemplified reaction. However, those skilled in the art can use various methods to prepare the compound of formula 1 in accordance with the structural formula of Formula 1, and such methods are still within the scope of the present invention. That is, the compound of Formula 1 can be prepared by the methods described herein or by various methods disclosed in the related art, and should still be within the scope of the present invention. Therefore, the method of preparing the compound of Formula 1 is not limited by the following methods.

Wherein, RA, RB, Ar, A, B, R1, R2 and n are as described above, and X represents a leaving group, preferably a halogen, a mesylate (-OMs), and the like.

Reaction Scheme 1 will be explained in more detail below.

Compound 4 is prepared by reacting Compound 2 with Compound 3 in the presence of a conventional base or an organometallic catalyst. Compound 5 is prepared from Compound 4 by a conventional reduction method and a deprotection reaction.

Compound 7 can be obtained from Compound 6 by a Mitsunobu reaction using N-hydroxy quinone. Compound 8 is then reacted with a conventional amine deprotecting agent such as hydrazine or alkylhydrazine to give compound 8. The conventional condensation reaction is carried out from the intermediate compounds 5 and 8, to obtain the formula 1 Things.

Alternatively, a compound of formula 1 according to the invention may be prepared according to the following reaction.

Among them, RA, RB, Ar, A, B, R1, R2, n and X are all as described above.

Reaction of compound 5 with hydroxylamine produces ruthenium compound 5-1, followed by a light extension reaction with compound 6, to yield compound 1. Alternatively, compound 1 can be prepared by reacting hydrazine compound 5-1 with intermediate compound 6-1 substituted with a leaving group X.

In the above reaction, a conventional metal base and an organic base can be used. Examples of bases include, but are not limited to, metal bases such as sodium hydride (NaH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs ₂ CO ₃ ), sodium carbonate (Na ₂ CO) ₃ ) and potassium carbonate (K ₂ CO ₃ ), and organic bases such as diisopropylethylamine, triethylamine and 1,8-diazobicyclo[5,4,0]undec-7 -ene (DBU).

The above reaction can be carried out in a conventional solvent which does not adversely affect the reaction. Preferred solvents include, but are not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, water, 1,2-dichloroethane, dimethyl hydrazine, diethyl ether, Methyl tertiary butyl ether, dichloromethane, chloroform, and mixtures thereof.

In the above reaction, the unexplained compound is a known compound or a compound which can be easily obtained by a known method or the like.

The compound of the formula 1 obtained by the above method can be isolated or purified from the reaction product by a conventional method such as recrystallization, iontophoresis, ruthenium column chromatography or ion exchange chromatography.

As stated above, the compounds according to the invention, the starting materials or intermediates for the preparation of such compounds can be prepared according to various methods, which are still within the scope of the invention.

The compound of formula 1 according to the invention has the effect of a GPRl 19 agonist. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula 1, a pharmaceutically acceptable salt thereof or an isomer thereof as an active ingredient, as an agonist of GPR119.

Examples of diseases which can be prevented or treated by using the pharmaceutical composition according to the present invention as a GPR119 agonist include, but are not limited to, diabetes, diabetic complications, obesity, dyslipidemia, osteoporosis, and the like. The pharmaceutical composition of the present invention can be used for preventing or treating type 1 or type 2 diabetes, and particularly preferably for preventing or treating type 2 diabetes. Specifically, the present invention provides A composition for lowering blood glucose concentration comprising an effective amount of a compound of formula 1, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier.

Further, the present invention provides a method for preparing a composition for preventing or treating diabetes, diabetic complications, obesity, dyslipidemia or osteoporosis, which comprises the steps of: a compound of formula 1 as an active ingredient, which is pharmaceutically acceptable The salt or isomer is accepted and mixed with a pharmaceutically acceptable carrier.

According to the present invention, the "pharmaceutical composition" or "composition for lowering blood sugar concentration" may include a carrier, a diluent, an excipient or a combination thereof in addition to the active ingredient of the present invention. Accordingly, the pharmaceutical composition can include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof as desired. The pharmaceutical composition facilitates administration of the compound to the body. Various methods of administering a compound include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration.

As used herein, "carrier" means a compound that promotes the addition of a compound into a cell or tissue. For example, dimethyl sulfoxide is a carrier used to facilitate administration of a compound to cells or tissues.

As used herein, "diluent" means a compound which is not only stable to a biologically active form but also soluble in a solvent in which the compound is dissolved. A buffer solution in which a salt is dissolved is a diluent used in the field. The commonly used buffering agent is a physiological saline solution for simulating a salt type phosphate buffer in a body fluid. Since the buffer solution can control the pH of the solution at a low concentration, the buffer diluent hardly changes the biological activity of the compound.

As used herein, "pharmaceutically acceptable" means that this property does not impair the combination. Biological activity and physical properties of the substance.

The compounds according to the invention can be formulated into a variety of different pharmaceutical dosage forms. When preparing a pharmaceutical composition of the invention, the active ingredient (specifically, a compound of formula 1), a pharmaceutically acceptable salt or isomer thereof, is admixed with a pharmaceutically acceptable carrier selected for the dosage form to be prepared. . For example, the pharmaceutical composition of the present invention can be formulated into an injection, an oral preparation, and the like as needed.

The compounds of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients, and then loaded into units or units of containers. The formulation may be a solution, suspension or emulsion contained in an oily or aqueous solvent, and includes conventional dispersing, suspending or stabilizing agents. Further, the compound may, for example, be in a dry powder form and dissolved in sterile pyrogen-free water prior to use. The compounds of the present invention can be formulated into a suppository using a conventional suppository with a base such as cocoa butter or other glycerides. Oral administration solid forms include capsules, lozenges, pills, powders, and granules. Capsules and lozenges are preferred. Lozenges and pills are preferably coated with an enteric coating. The solid dosage form is prepared by mixing a compound of the invention with at least one carrier selected from the group consisting of inert diluents (eg, sucrose, lactose, or starch), lubricants (eg, magnesium stearate), disintegrating agents, combinations. Agents, and the like.

If desired, the compounds according to the invention may be administered in combination with other drugs, for example, other anti-diabetic agents.

The dosage of the compound according to the invention is determined by the physician in consideration of the weight, age and disease state of the patient. Depending on the frequency and intensity of administration, typical doses for adults range from about 0.3 to 500 mg per day. A typical daily dose for a person who is administered intramuscularly or intravenously in an adult is about 1 to 300 mg per day. It can be administered in divided unit doses. Some patients require a higher daily dose.

The present invention also provides a method of preventing or treating a disease by using an effective amount of a compound of the formula 1, a pharmaceutically acceptable salt or isomer thereof as an active ingredient of the GPR119 agonist. Representative diseases that can be treated with the GPRl 19 agonist include, but are not limited to, metabolic abnormalities such as diabetes, diabetic complications, obesity, dyslipidemia, osteoporosis, and the like. As used herein, "treatment" is used to mean the delay, delay, or alleviation of the progression of a disease that has occurred. The term "prevention" is used to mean the prevention, delay or alleviation of the disease in an individual at risk of developing a symptom of the disease, even when symptoms have not yet occurred.

The hydrazine derivative of the formula I according to the present invention can stimulate the pancreas to secrete insulin and promote the formation of GLP-1, PYY and GIP in the gastrointestinal tract, and thus can be effectively used for preventing or treating diabetes, diabetic complications, obesity, dyslipidemia or osteoporosis. disease.

The following examples illustrate the invention in more detail. However, the examples are for illustrative purposes only and are not intended to limit the scope of the invention. Hereinafter, M means a molar concentration, and N means an equivalent concentration.

Preparation Example 1: 8-(2,5-Difluoro-4-nitro-phenyl)-1,4-dioxa-spiro[4.5]indole-7-ene

4-Bromo-2,5-difluoronitrobenzene (19.82 g, 83.28 mmol) was dissolved in 1,4-two After alkane (410 mL), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro [4.5] 癸-7-ene (26 g, 99.88 mmol). After the addition of dichlorobis(triphenylphosphine)palladium(2) (2.9 g, 4.16 mmol), 1.0 M sodium carbonate (250 mL, 249.85 mmol) was added. The mixture was evacuated using a vacuum pump and flushed with nitrogen. The mixture was refluxed at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction was quenched with water, filtered with celite, and washed with ethyl acetate, water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

NMR: ¹ H-NMR (CDCl ₃ ) 7.81 to 7.77 (1H, m), 7.24 to 7.00 (1H, m), 6.11 (1H, m), 4.03 (4H, s), 2.64 to 2.61 (2H, m) , 2.52~2.51(2H,m),1.92(2H,t)

Preparation 2: 4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-phenylamine

8-(2,5-Difluoro-4-nitro-phenyl)-1,4-dioxa-spiro[4.5]indole-7-ene (21.1 g, 70.8 mmol) from Preparation Example 1. Dissolved in ethyl acetate/methanol (8/2) (354 mL), 10% palladium / char (3.5 g). The mixture was evacuated using a vacuum pump and stirred under hydrogen for 12 hours. The mixture was filtered through EtOAc EtOAc (EtOAc)

NMR: ¹ H-NMR (CDCl ₃ ) 6.88 to 6.83 (1H, m), 6.47 to 6.42 (1H, m), 3.97 (4H, s), 3.67 (2H, s), 2.79 (1H, m), 1.83 ~1.75(4H,m), 1.74~1.65(4H,m)

Preparation Example 3: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone

4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-phenylamine (10 g, 37.13 mmol) from Preparation 2 was dissolved in dichloromethane (50mL), Trifluoroacetic acid (30 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 5 hr. The solvent in the mixture was removed under reduced pressure, and the mixture was washed with ethyl acetate, water and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

NMR: ¹ H-NMR (CDCl ₃ ) 6.83 to 6.78 (1H, m), 6.50 to 6.45 (1H, m), 3.73 (2H, s), 3.25 to 3.18 (1H, m), 2.60 to 2.55 (4H, m), 2.27~2.10(2H,m), 1.90~1.80(2H,m)

Preparation 4: 4-Aminooxy-piperidine-1-carboxylic acid tert-butyl ester

Triphenylphosphine (4.17 g, 17.97 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0. N,N-azodicarboxylic acid diisopropyl ester (3 mL) was added dropwise, and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3 g, 14.9 mmol) was added, and the mixture was stirred for 30 minutes. Hydroxyimine (2.46 g, 15.12 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was distilled under reduced pressure to remove the solvent, and purified by column chromatography using hexane, methylene chloride and ethyl acetate 5:5:1 to give 4-(1,3-di- oxy-1) , 3-Dihydro-isoindol-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (3.11 g, 60% yield). The obtained compound (3.11 g, 8.97 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0. Methyl hydrazine (0.53 g, 11.67 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to EtOAc.

NMR: ¹ H-NMR (CDCl ₃ ) 5.55 to 5.20 (2H, br), 3.81 to 3.65 (3H, m), 3.11 to 3.01 (2H, m), 1.95 to 1.81 (2H, m), 1.58 to 1.50 ( 2H, m), 1.46 (9H, s)

Preparation 5: 4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (28 g, 78.49 mmol) from Preparation 3 was dissolved in tetrahydrofuran / methanol / water (3 / 2 / 1) 400 mL), tert-butyl 4-aminooxy-piperidine-1-carboxylate (17.82 g, 82.41 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The solvent in the mixture was removed under reduced pressure and the mixture was washed with ethyl acetate, water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous MgSO.sub.

NMR: ¹ H-NMR (CDCl ₃ ) 6.78-6.73 (1H, m), 6.48-6.40 (1H, m), 4.19 (1H, m), 3.80 to 3.70 (4H, m), 3.41 to 3.40 (1H, m), 3.28~3.20(2H,m), 2.96(1H,m), 2.49~2.46(1H,m), 2.35~2.22(1H,m),2.00~1.80(5H,m),1.70~1.58( 2H,m), 1.46(9H,s), 1.45~1.43(2H,m)

Preparation 6: O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine

4-Hydroxy-piperidine (2.0 g, 19.8 mmol), 2-chloro-5-methyl-pyrimidine (2.8 g, 19.38 mmol) and triethylamine (5.5 mL, 39.5 mmol) were dissolved in dimethyl Indoleamine (100 mL). The temperature was raised to 100 ° C and the mixture was stirred for 5 hours. The temperature was changed to room temperature, and water and ethyl acetate were added. The mixture was extracted three times with ethyl acetate (100 mL), then evaporated and evaporated, evaporated, evaporated, and evaporated. -yl)-piperidin-4-ol (2.5 g, 65% yield). By 1-(5-A </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 5.33 (2H, s), 4.32 to 4.22 (2H, m), 3.83 to 3.74 (1H, m), 3.37 to 3.27 (2H, m) , 2.11 (3H, s), 2.03~1.94 (2H, m), 1.62~1.50 (2H, m)

Preparation 7: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl ]-肟

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (2.85 g, 7.93 mmol) from Preparation Example 3 and O-[1-(5-methyl-pyrimidine- 2-Base)-piperidin-4-yl]-hydroxylamine (2.05 g, 9.51 mmol).

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, m), 6.78 to 6.73 (1H, m), 6.48 to 6.40 (1H, m), 4.29 (1H, m), 4.14 to 4.08 (2H, m) , 3.68 (2H, s), 3.52~3.47 (2H, m), 3.44~3.41 (1H, m), 2.97 (1H, m), 2.52~2.49 (1H, m), 2.30~2.20 (1H, m) , 2.10 (3H, s), 2.05~1.90 (4H, m), 1.80~1.70 (1H, m), 1.75~1.65 (2H, m), 1.60~1.40 (2H, m)

Preparation 8: O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine

Reaction of 5-ethyl-2-chloro-pyrimidine (7.1 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol)

NMR: ¹ H-NMR (CDCl ₃ ) 8.11 (2H, s), 5.31 (2H, s), 4.24 (2H, m), 3.74 (1H, m), 3.28 (2H, m), 2.42 (2H, m) ), 1.94 (2H, m), 1.53 (2H, m), 1.14 (3H, t)

Preparation 9: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl ]-肟

O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (0.44 g, 2 mmol) and 4-(4-amino)- 2,5-Difluoro-phenyl)-cyclohexanone was reacted according to the procedure of Preparation 5 to give the title compound (0.81 g, 90% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 6.76 (1H, m), 6.42 (1H, m), 4.28 (1H, m), 4.13 (2H, m), 3.73 (2H, s ), 3.51 (2H, m), 3.42 (1H, d), 2.95 (1H, t), 2.52~2.38 (3H, m), 2.24 (1H, m), 2.10~1.90 (4H, m), 1.88 ( 1H, m), 1.69 (2H, m), 1.62~1.48 (2H, m), 1.17 (3H, t)

Preparation 10: 4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

Reaction of 1-chloro-2-fluoro-4-nitro-benzene (360 mg, 2.05 mmol) in EtOAc (m. %).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, m), 6.94 (1H, t), 6.42 to 6.34 (2H, m), 4.29 (1H, m), 4.14 to 4.08 (2H, m), 3.68 (2H, s), 3.52~3.47(2H,m), 3.44~3.41(1H,m), 2.97(1H,m),2.52~2.49(1H,m), 2.30~2.20(1H,m),2.10 (3H, s), 2.05~1.90 (4H, m), 1.80~1.70 (1H, m), 1.75~1.65 (2H, m), 1.60~1.40 (2H, m)

Preparation 11: O-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yl]-hydroxylamine

4-Hydroxypiperidine (3.0 g, 29.7 mmol) was taken in dichloromethane (90 mL) and cooled to 0. Sodium hydrogencarbonate (10.0 g, 119 mmol) was dissolved in water (30 mL) and then added. After 30 minutes, cyano bromide (3.8 g, 35.6 mmol) was dissolved in dichloromethane (30 mL). The temperature was raised to room temperature and the mixture was stirred for 2 hours. The reaction was quenched with water and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO.sub.

4-Hydroxy-piperidine-1-carbonitrile (2.0 g, 15.9 mmol) and N-hydroxy-isobutyl hydrazine (2.1 g, 20.6 mmol) were dissolved in ethyl acetate (53 mL) and 1N zinc chloride was slowly added. A solution of diethyl ether (20.6 mL, 20.6 mmol). The mixture was stirred for 15 min and diethyl ether was added to give a white solid. Concentrated hydrochloric acid (5 mL) and ethanol (10 mL) were added to the obtained solid, and the mixture was refluxed for 1 hour. The ethanol was distilled off under reduced pressure, and the mixture was neutralized by adding an aqueous sodium carbonate solution. After extracting with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate and evaporated. The mixture was subjected to column chromatography using a 1:1 mixture of ethyl acetate and hexane to give 1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-ol (1.0 g, 30%). From 1-(3-isopropyl-[1,2,4] The oxazol-5-yl)-piperidin-4-ol (1.0 g, 4.73 mmol

NMR: ¹ H-NMR (CDCl ₃ ) 3.99 to 3.89 (3H, m), 3.40 to 3.34 (2H, m), 2.92 to 2.84 (1H, m), 1.99 to 1.92 (2H, m), 1.67 to 1.59 ( 2H,m), 1.56(2H,s), 1.28(6H,d)

Preparation 12: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yl]-indole

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (0.60 g, 2.7 mmol) from Preparation Example 3 and O-[1-(3) from Preparation 11 -isopropyl-[1,2,4] The oxazol-5-yl)-piperidin-4-yl]-hydroxylamine (0.6 g, 2.7 mmol.

NMR: ¹ H-NMR (CDCl ₃ ) 6.81 to 6.73 (1H, m), 6.47 to 6.42 (1H, m), 4.32 to 4.26 (1H, m), 3.81 to 3.68 (4H, m), 3.54 to 3.48 ( 2H,m), 3.41~3.35(1H,m),2.96(1H,t),2.91~2.83(1H,m),2.52~2.47(1H,m),2.28~2.20(1H,m),2.05~ 1.91(4H,m), 1.90~1.75(3H,m),1.61~1.54(2H,m),1.28(6H,d)

Preparation 13: 1-thiazol-2-yl-piperidin-4-ol

2-Bromothiazole (1.0 g, 6.10 mmol) was dissolved in N,N-dimethylformamide (20 mL), piperidin-4-ol (925 mg, 9.15 mmol) and DBU (2.73 mL, 18.29 mmol) The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL) andEtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, evaporated

NMR: ¹ H-NMR (CDCl ₃ ) 7.48 (1H, d), 6.55 (1H, d), 3.96 (1H, m), 3.85 (2H, m), 3.26 (2H, m), 1.99 (2H, m) ), 1.68 (2H, m)

Preparation 14: 2-(1-thiazol-2-yl-piperidin-4-yloxy)-isoindole-1,3-dione

The 1-thiazol-2-yl-piperidin-4-ol (240 mg, 1.30 mmol) from Preparation 13 was dissolved in tetrahydrofuran (20 mL), and 2-hydroxy-isoindole-1,3-di was slowly added. Ketone (2.34 mg, 1.43 mmol) and triphenylphosphine (410 mg, 1.56 mmol).

Diisopropyl azodicarboxylate (0.3 mL, 1.56 mmol) was slowly added dropwise at 0 ° C and the mixture was stirred at room temperature for 3 days. The reaction mixture was evaporated to dryness crystals crystals crystals crystals

NMR: ¹ H-NMR (CDCl ₃ ) 7.85 (2H, m), 7.77 (2H, m), 7.19 (1H, d), 6.57 (1H, d), 4.50 (1H, m), 3.94 (2H, m ), 3.41 (2H, m), 2.08 (4H, m)

Preparation 15: O-(1-thiazol-2-yl-piperidin-4-yl)-hydroxylamine

2-(1-thiazol-2-yl-piperidin-4-yloxy)-isoindole-1,3-dione (460 mg, 1.40 mmol) from Preparation 14 was dissolved in dichloromethane. 20 mL), hydrazine (0.1 mL, 2.09 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered. The obtained compound was used in the next reaction without further purification.

Quality (EI) 200 (M ⁺ +1)

Preparation 16: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-(1-thiazol-2-yl-piperidin-4-yl)-indole

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (200 mg, 1.03 mmol) from Preparation Example 3 and O-(1-thiazole-2 from Preparation 15 -Methyl-piperidin-4-yl)-hydroxylamine (256 mg, 1.03 mmol).

NMR: ¹ H-NMR (CDCl ₃ ) 7.18 (1H, d), 6.77 (1H, m), 6.55 (1H, d), 6.45 (1H, m), 4.31 (1H, m), 3.73 (4H, m ), 3.40 (3H, m), 2.98 (1H, m), 2.53 (1H, m), 2.24 (1H, m), 2.06 to 1.95 (4H, m), 1.85 (3H, m), 1.64 to 1.46 ( 2H,m)

Preparation 17: 4-Hydroxy-piperidine-1-thiocarboxylic acid (2-bromo-phenyl)-decylamine

1-Bromo-2-isothiocyanato-benzene (500 mg, 2.34 mmol) was dissolved in dichloromethane (20 mL). The solvent of the reaction mixture was evaporated under reduced pressure.

NMR: ¹ H-NMR (CDCl ₃ ) 7.63 (1H, m), 7.57 (1H, m), 7.30 (1H, m), 7.18 (1H, s), 7.02 (1H, m), 4.16 (2H, m) ), 4.06 (1H, m), 3.71 (2H, m), 1.97 (2H, m), 1.69 (2H, m)

Preparation 18: 1-Benzothiazol-2-yl-piperidin-4-ol

The compound from Preparation 17 (810 mg, 2.57 mmol) was dissolved in dimethoxyhexane (20 mL). Copper iodide (24 mg, 0.13 mmol), 1,10-phenanthroline (46 mg, 0.26 mmol) and cesium carbonate (1.67 g, 5.14 mmol) were added, and the mixture was stirred at 70 ° C for 3 hours. The reaction mixture was filtered over EtOAc EtOAc (EtOAc)

NMR: ¹ H-NMR (CDCl ₃ ) 7.60 (1H, m), 7.55 (1H, m), 7.31 (1H, m), 7.05 (1H, m), 4.40 (3H, m), 3.41 (2H, m ), 2.02 (2H, m), 1.70 (2H, m), 1.52 (1H, d)

Preparation 19: 2-(1-Benzothiazol-2-yl-piperidin-4-yloxy)- Iso-1,3-dione

The 1-benzothiazol-2-yl-piperidin-4-ol (550 mg, 2.35 mmol) from mp.

NMR: ¹ H-NMR (CDCl ₃ ) 7.87 (2H, m), 7.78 (2H, m), 7.61 (1H, m), 7.56 (1H, m), 7.31 (1H, m), 7.08 (1H, m) ), 4.55 (1H, m), 4.06 (2H, m), 3.60 (2H, m), 2.11 (4H, m)

Preparation 20: O-(1-benzothiazol-2-yl-piperidin-4-yl)-hydroxylamine

The 2-(1-benzothiazol-2-yl-piperidin-4-yloxy)-isoindole-1,3-dione obtained in Preparation Example 19 was reacted in a similar manner to Preparation 15 to give The title compound (450 mg, 77% yield in two steps).

NMR: ¹ H-NMR (CDCl ₃ ) 7.60 (1H, m), 7.55 (1H, m), 7.31 (1H, m), 7.08 (1H, m), 5.35 (2H, m), 3.91 to 3.79 (3H) , m), 3.45 (2H, m), 2.04 (2H, m), 1.77 (2H, m)

Preparation 21: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-(1-benzothiazol-2-yl-piperidin-4-yl)-indole

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (204 mg, 1.03 mmol) from Preparation Example 3 and O-(1-benzothiazole from Preparation Example 20 The reaction of the title compound (180 mg, 87% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 7.60 (1H, m), 7.53 (1H, m), 7.31 (1H, m), 7.08 (1H, m), 6.80 (1H, m), 6.48 (1H, m ), 4.36 (1H, m), 3.84 (2H, m), 3.70 (2H, s), 3.55 (2H, m), 3.43 (1H, m), 2.98 (1H, m), 2.53 (1H, m) , 2.24 (1H, m), 2.09~ 1.95 (4H, m), 1.88 (3H, m), 1.64~1.49 (2H, m)

Preparation 22: Benzyl (4-bromo-2,6-difluoro-phenyl)-aminecarboxylate

4-Bromo-2,6-difluoro-phenylamine (1 g, 4.80 mmol) was dissolved in tetrahydrofuran (15 mL) and sodium bicarbonate (483 mg, 5.76 mmol) was added dropwise at 0 °C. The benzyl chloroformate (800 mg, 5.76 mmol) was added dropwise and the mixture was stirred at room temperature for 12 hr. The reaction was quenched with water and the mixture was washed with diethyl ether, water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

NMR: ¹ H-NMR (CDCl ₃ ) 7.39~7.34 (5H, m), 7.17~7.13 (2H, m), 6.07 (1H, s), 5.21. (2H, s)

Preparation 23: 4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl ]-肟

The benzyl (4-bromo-2,6-difluoro-phenyl)-carbamic acid benzyl ester (489 mg, 1.43 mmol) was obtained according to the procedure of Preparations 1, 2, 3 and 7 to give the title compound (354 mg, The total yield of the four steps was 68%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, m), 6.71 to 6.66 (2H, m), 4.29 (1H, m), 4.14 to 4.08 (2H, m), 3.68 (2H, s), 3 , 52~3.47(2H,m), 3.44~3.41(1H,m), 2.79(1H,m), 2.62~2.52(1H,m), 2.23~2.18(1H,m),2.10(3H,s) , 2.05~1.90(4H,m), 1.80~1.70(1H,m),1.75~1.65(2H,m),1.60~1.40(2H,m)

Preparation 24: 4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

1-Chloro-2-fluoro-4-nitro-benzene (360 mg, 2.05 mmol) was obtained according to the procedure of Preparations 1, 2, 3, and 9 to give the title compound (570 mg, %).

NMR: ¹ H-NMR (CDCl ₃ ) 8.17 (2H, m), 6.94 (1H, t), 6.42 to 6.34 (2H, m), 4.29 (1H, m), 4.14 to 4.08 (2H, m), 3.68 (2H, s), 3.52~3.47(2H,m), 3.44~3.41(1H,m), 2.97(1H,m),2.52~2.40(3H,m), 2.30~2.20(1H,m),2.07 ~1.90(4H,m), 1.90~1.80(1H,m),1.75~1.65(2H,m),1.60~1.40(2H,m),1.18(3H,m)

Preparation 25: O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine

4-Hydroxy-piperidine (5.0 g, 49.3 mmol) and 2,5-dichloro-pyrimidine (7.2 g, 48.3 mmol)yield .

NMR: ¹ H-NMR (CDCl ₃ ) 8.20 (2H, s), 5.33 (2H, s), 4.24 to 4.17 (2H, m), 3.83 to 3.76 (1H, m), 3.41 to 3.32 (2H, m) , 2.01~1.92(2H,m), 1.62~1.53(2H,m)

Preparation 26: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl] -肟

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (0.26 g, 1.1 mmol) from Preparation Example 3 and O-[1-(5) from Preparation 25 -Chloro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (m.p.)

NMR: ¹ H-NMR (CDCl ₃ ) 8.21 (2H, s), 6.80 to 6.73 (1H, m), 6.48 to 6.42 (1H, m), 4.32 to 4.28 (1H, m), 4.15 to 4.05 (2H, m), 3.80~3.54(4H,m), 3.45~3.38(1H,m), 2.97(1H,t),2.53~2.48(1H,m),2.92~2.21(1H,m),2.05~1.92( 4H,m), 1.91~1.79(1H,m), 1.78~1.65(2H,m),1.64~1.48(2H,m)

Preparation 27: 4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-oxime

1-Chloro-2-fluoro-4-nitro-benzene (360 mg, 2.05 mmol) was obtained according to the procedure of Preparations 1, 2, 3, and 26 to give the title compound (530 mg, 4 %).

NMR: ¹ H-NMR (CDCl ₃ ) 8.21 (2H, s), 6.96 to 6.93 (1H, m), 6.41 to 6.30 (2H, m), 4.30 (1H, m), 4.15 to 4.05 (2H, m) , 3.70~3.51(4H,m), 3.40(1H,m), 3.00(1H,m),2.55(1H,m),2.35~2.25(1H,m),2.10~1.90(4H,m),1.95 ~1.85(1H,m), 1.78~1.60(2H,m), 1.50~1.40(2H,m)

Preparation 28: O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl)-hydroxylamine

5-Trifluoromethyl-2-chloro-pyridine (9.05 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol) ).

NMR: ¹ H-NMR (CDCl ₃ ) 8.37 (1H, s), 7.60 (1H, m), 6.65 (1H, d), 5.33 (2H, s), 4.02 (2H, m), 3.81 (1H, m ), 3.36 (2H, m), 1.98 (2H, m), 1.64 (2H, m)

Preparation 29: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2']bipyridin-4-yl)-oxime

O-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl)-hydroxylamine (492 mg, obtained from Preparation 28) The title compound (0.88 g, 94% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 8.38 (1H, s), 7.59 (1H, m), 6.79 (1H, m), 6.67 (1H, d), 6.45 (1H, m), 4.32 (1H, m ), 3.92 (2H, m), 3.70 (2H, s), 3.49 (2H, m), 3.42 (1H, d), 2, 99 (1H, t), 2.52 (1H, d), 2.27 (1H, m), 2.10~1.92 (4H, m), 1.92~1.48 (5H, m)

Preparation 30: 4-(4-Amino-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

1-Chloro-4-nitro-benzene (200 mg, 1.269 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, m), 7.01 to 6.99 (2H, m), 6.65 to 6.63 (2H, m), 4.29 (1H, m), 4.14 to 4.08 (2H, m) , 3.62~3.47(4H,m), 3.44~3.41(1H,m), 2.70(1H,m),2.52~2.49(1H,m), 2.30~2.20(1H,m),2.10(3H,s) , 2.05~1.90(4H,m), 1.80~1.70(1H,m),1.75~1.65(2H,m),1.60~1.40(2H,m)

Preparation 31: 4-[4-(4-Amino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester

1-Chloro-4-nitro-benzene (200 mg, 1.269 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.01 to 6.99 (2H, m), 6.65 to 6.63 (2H, m), 4.20 (1H, m), 3.78 to 3.65 (2H, m), 3.55 (2H, m) , 3.44~3.41(1H,m), 3.30~3.18(2H,m), 2.73(1H,m),2.52~2.49(1H,m), 2.30~2.20(1H,m),2.10~1.94(2H, m), 1.94~1.79(3H,m), 1.75~1.65(4H,m), 1.46(9H,s)

Preparation 32: 4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester from Preparation Example 5. (862 mg, 2.035 mmol) was dissolved in dichloromethane (4 mL). Add 4N HCl/1,4-two at 0 °C The mixture was stirred (1 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was distilled under reduced pressure and dried under high pressure. Dichloromethane (15 mL) was added, isopropyl chloroformate (800 mg, 0.800 mmol) was added dropwise at 0 ° C, triethylamine (1.4 mL, 13.85 mmol) was added, and the mixture was stirred and reacted for 10 minutes. The reaction was quenched with water and the mixture was washed with ethyl acetate, water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

NMR: ¹ H-NMR (CDCl ₃ ) 6.78~6.73 (1H, m), 6.48~6.40 (1H, m), 4.90 (1H, m), 4.20 (1H, m), 3.78~3.60 (4H, m) , 3.44~3.41(1H,m), 3.30~3.20(2H,m), 3.00(1H,m),2.52~2.49(1H,m), 2.30~2.20(1H,m),2.10~1.80(4H, m), 1.70~1.45(5H,m), 1.23(6H,d)

Preparation 33: 4-(1,4-Dioxa-spiro[4.5]indole-7-ene-8-yl)- 2,5-difluoro-benzoic acid methyl ester

Take 4-bromo-2,5-difluoro-benzoic acid methyl ester (152 mg, 0.735 mmol) and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Hexane-2-yl)-1,4-dioxaspiro[4.5]indole-7-ene (195 mg, 0.735 mmol)yield .

NMR: ¹ H-NMR (CDCl ₃ ) 7.61~7.57 (1H, m), 7.08~7.00 (1H, m), 6.05 (1H, m), 4.02 (4H, s), 3.92 (3H, s), 2.62 (2H,m), 2.49(2H,m),1.92(2H,t)

Preparation 34: 4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-benzoic acid methyl ester

4-(1,4-Dioxa-spiro[4.5]indole-7-en-8-yl)-2,5-difluoro-benzoic acid methyl ester (91 mg, 0.293 mmol) from Preparation 33 The title compound (90 mg, 99% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7, 58 - 7.56 (1H, m), 7.05 - 7.02 (1H, m), 3.97 (4H, s), 3.92 (3H, s), 2.92 (1H, m) , 1.87~1.80(4H,m), 1.74~1.65(4H,m)

Preparation 35: 2,5-Difluoro-4-(4-o-oxy-cyclohexyl)-benzoic acid methyl ester

4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2,5-difluoro-benzoic acid methyl ester (90 mg, 0.288 mmol) from Preparation 34, according to Preparation The title compound (76 mg, 99% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.64~7.60 (1H, m), 7.02~6.98 (1H, m), 3.93 (3H, s), 3.11 (1H, m), 2.56~2.53 (4H, m) , 2.23 (2H, m), 1.97 (2H, m)

Preparation 36: 4-[4-(4-carboxy-2,5-difluoro-phenyl)-cyclohexylideneaminooxy-piperidine-1-carboxylic acid tert-butyl ester

4-[4-(2,5-Difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl group from Example 10 The ester (3.12 g, 6.673 mmol) was added and dissolved in tetrahydrofuran / methanol / 1N sodium hydroxide (1/1/1) solution (30 mL), and the mixture was stirred at room temperature for 1 hour and then distilled under reduced pressure. The aqueous layer was acidified with aq. EtOAc (EtOAc)EtOAc. The organic layer was dried (MgSO4)

NMR: ¹ H-NMR (MeOD) 7.59 to 7.55 (1H, m), 7.18 to 7.14 (1H, m), 4.23 (1H, m), 3.75 to 3.65 (2H, m), 3.50 to 3.40 (1H, m ), 3.30~3.20(2H,m), 3.09(1H,m), 2.60~2.50(1H,m), 2.30~2.20(1H,m),2.10~2.00(2H,m),1.95~1.80(3H , m), 1.70~1.60(4H,m), 1.46(9H,s)

Preparation 37: O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine

Reaction of 5-propyl-2-chloro-pyrimidine (7.8 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol)

NMR: ¹ H-NMR (CDCl ₃ ) 8.13 (2H, s), 5.32 (2H, s), 4.29 (2H, m), 3.79 (1H, m), 3.33 (2H, m), 2.39 (2H, ), 1.99 (2H, m), 1.62~1.50 (4H, m), 0.93 (3H, t)

Preparation 38: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl ]-肟

O-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (0.47 g, 2 mmol) from Preparation 37 was reacted according to the method of Preparation 5. The title compound (0.86 g, 97% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 8.13 (2H, s), 6.78 (1H, m), 6.44 (1H, m), 4.29 (1H, m), 4.14 (2H, m), 3.71 (2H, s ), 3.52 (2H, m), 3.41 (1H, d), 2.98 (1H, t), 2.51 (1H, d), 2.38 (2H, t), 2.17 (1H, m), 2.10~1.91 (4H, m), 1.88 (1H, m), 1.69 (2H, m), 1.63~1.44 (4H, m), 0.91 (3H, t)

Preparation 39: O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine

5-Fluoro-2-chloro-pyrimidine (6.6 g, 50 mmol) and 4-hydroxypiperidine (5.05 g, 50 mmol. The obtained compound was used in the next reaction without further purification.

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 5.33 (2H, s), 4.22 (2H, m), 3.78 (1H, m), 3.36 (2H, m), 1.98 (2H, m) ), 1.58 (2H, m)

Preparation 40: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl] -肟

The O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (0.42 g, 2 mmol) from Preparation 39 was reacted according to the procedure of Preparation 5. Compound (0.79 g, 94% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 8.17 (2H, s), 6.78 (1H, m), 6.45 (1H, m), 4.29 (1H, m), 4.10 (2H, m), 3.69 (2H, s ), 3.54 (2H, m), 3.42 (1H, m), 3.00 (1H, t), 2.52 (1H, m), 2.26 (1H, m), 2.06 to 1.90 (4H, m), 1.89 (1H, m), 1.71 (2H, m), 1.66~1.48 (2H, m)

Preparation 41: 4-{4-[4-(1,3-Di-Ethyloxy-1,3-dihydro-isoindol-2-ylmethyl)-2,5-difluoro-phenyl] - cyclohexylaminooxy}-piperidine-1-carboxylic acid isopropyl ester

4-[4-(2,5-Difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Example 9 ( 70 mg, 0.16 mmol), quinone (26 mg, 0.18 mmol), diisopropylethylamine (35 μl, 0.18 mmol) and triphenylphosphine (47 mg, 0.18 mmol) dissolved in tetrahydrofuran (5 mL) The mixture was stirred at temperature for 12 hours and the reaction was stopped. The reaction mixture was washed with ethyl acetate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous MgSO.

^{1 H-NMR (400MHz, CDCl} 3); 7.90 (2H, m), 7.77 (2H, m), 7.02 (1H, m), 6.90 (1H, m), 4.92 (1H, m), 4.88 (2H, s), 4.24 (1H, m), 3.71 (2H, m), 3.46 (1H, d), 3.30 (2H, m), 3.05 (1H, t), 2.50 (1H, d), 2.24 (1H, m) ), 2.05 (5H, m), 1.65 (4H, m), 1.27 (6H, d)

Preparation 42: 4-[4-(4-Aminomethyl-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-{4-[4-(1,3-Di- oxy-1,3-dihydro-isoindol-2-ylmethyl)-2,5-difluoro-- obtained from Preparation 41 Phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester (120 mg, 0.2 mmol), hydrazine (52 μl, 1.0 mmol) and ethanol (1 mL) were stirred in dichloromethane (1 mL) for 24 hr. The reaction mixture was washed with ethyl acetate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous MgSO.

^{1 H-NMR (400MHz, CDCl} 3); 7.05 (1H, m), 6.88 (1H, m), 4.92 (1H, m), 4.22 (1H, m), 3.85 (2H, s), 3.71 (2H, m), 3.45 (1H, d), 3.28 (2H, m), 3.08 (1H, m), 2.54 (1H, d), 2.26 (1H, m), 2.05 (1H, m), 1.89 (4H, m ), 1.65 (4H, m), 1.26 (6H, d)

Preparation 43: [(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-1-(4-iodo-benzyl)-2-oxo-ethyl]- Tert-butyl carbamate

(S)-2-Tertoxycarbonylamino-3-(4-iodo-phenyl)-propionic acid (314 mg, 0.80 mmol) obtained from the product was dissolved in dichloromethane (15 mL). Adding S-3-fluoro-pyrrolidine hydrochloride (111 mg, 0.88 mmol), EDC (231 mg, 1.20 mmol), HOBT (184 mg, 1.20 mmol) and diisopropylethylamine (277 mg, 2.14 mmol), and The mixture was stirred at room temperature for 18 hours. After the reaction was quenched with saturated aqueous NaHCO ₃ was added, the organics extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure.

^{1 H-NMR (400MHz, CDCl} 3); δ 7.65 (dd, 2H), 7.02 (dd, 2H), 5.35 (m, 1H), 5.19 (d, 1H), 4.59 (m, 1H), 3.89 (m , 1H), 3.55~3.20 (m, 2H), 3.00 (m, 3H), 2.30 (m, 1H), 2.05~1.60 (m, 1H), 1.45 (d, 9H)

Preparation 44: [(S)-1-[4-(1,4-Dioxa-spiro[4,5]癸-8- Tert-butyl ester of benzyl)-benzyl]-2-((S)-3-fluoro-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid

[(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-1-(4-iodo-benzyl)-2-oxo-B, obtained from Preparation 43 The title compound (42 mg, 41% yield) was obtained from the title compound.

^{1 H-NMR (400MHz, CDCl} 3); δ 7.12 (m, 4H), 5.38 (dd, 1H), 5.05 (dd, 1H), 4.51 (m, 1H), 3.96 (s, 4H), 3.78 (m , 1H), 3.45~3.26 (m, 2H), 3.05~2.70 (m, 3H), 2.50 (m, 1H), 2.05 (m, 2H), 1.90~1.60 (m, 8H), 1.40 (d, 9H) )

Preparation 45: {(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-2-yloxy-1-[4-(4-o-oxy-cyclohexyl)- Tert-butyl ester of benzyl]-ethyl}-carbamic acid

[(S)-1-[4-(1,4-Dioxa-spiro[4,5]癸-8-yl)-benzyl]-2-((S)) from Preparation 44 3-Fluoro-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (42 mg, 0.088 mmol) dissolved in tetrahydrofuran (2 mL), water (1 mL) and acetic acid ( In 2 mL), the mixture was stirred at 70 ° C for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure, ethyl acetate was added, and the organic material was washed with saturated sodium carbonate. The org.

^{1 H-NMR (400MHz, CDCl} 3); δ 7.20 (m, 4H), 5.41 (m, 1H), 5.13 (dd, 1H), 4.60 (m, 1H), 3.86 (m, 1H), 3.70 ~ 3.30 (m, 2H), 3.00 (m, 4H), 2.53 (m, 4H), 2.20 (m, 3H), 2.10 to 1.75 (m, 3H), 1.45 (s, 9H)

Preparation 46: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidine-4 -基]-肟

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester from Preparation Example 5. (235 mg, 0.56 mmol) was dissolved in dichloromethane (4 mL). Add 4N HCl/1,4-two at 0 °C Alkane solution (3 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was distilled under reduced pressure and dried under high pressure. The dried mixture was dissolved in dimethylformamide (5 mL). 2-Chloro-4-trifluoromethylpyrimidine (122 mg, 0.67 mmol) and triethylamine (169 mg, 1.67 mmol) were added, and the mixture was reacted at 70 ° C for 2 hours. The reaction was quenched with water and the organic layer was extracted with diethyl ether. The organic layer was dried with EtOAc EtOAcjjjjjj

^{1 H-NMR (400MHz, CDCl} 3): δ 8.52 (d, 1H), 6.83 (dd, 1H), 6.76 (d, 1H), 6.50 (dd, 1H), 4.34 (m, 1H), 4.21 (m , 2H), 3.74 (s, 2H), 3.68 (m, 2H), 3.47 (m, 1H), 3.03 (m, 1H), 2.56 (m, 1H), 2.30 (td, 1H), 2.07 (m, 4H), 1.91 (td, 1H), 1.78 (m, 2H), 1.60 (m, 2H)

Preparation 47: 4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

4-Chloro-2-fluoro-1-nitrobenzene was reacted in the same manner as in Preparations 1, 2 and 3 to synthesize 4-(4-amino-3-fluoro-phenyl)-cyclohexanone. The synthesized compound (2.07 g, 10 mmol) and O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine (2.22 g, 10 mmol) according to the method of Preparation 5 to give the title compound (3.70 g, 90% yield rate).

NMR: ¹ H-NMR (CDCl ₃ ) 8.16 (2H, s), 6.85 (1H, d), 6.77 (1H, d), 6.72 (1H, t), 4.30 (1H, m), 4.15 (2H, m) ), 3.61 (2H, s), 3.52 (2H, m), 3.41 (1H, d), 3.65 (1H, t), 2.53~2.42 (3H, m), 2.22 (1H, m), 2.08~1.95 ( 4H, m), 1.88 (1H, m), 1.75~1.48 (2H, m), 1.19 (3H, t)

Preparation 48: 4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl ]-肟

4-Bromo-2,3-difluoro-phenylamine (3.02 g, 14.51 mmol) was obtained according to the procedure of Preparations 22, 1, 2, 3, and 9 to give the title compound (504 mg, 5 steps total) Yield 43%).

NMR: ¹ H-NMR (400 MHz, CDCl ₃ ): 8.16 (s, 2H), 6.70 (t, 1H), 6.76 (d, 1H), 4.30 (m, 1H), 4.15 (m, 2H), 3.71 ( s, 2H), 3.52 (m, 2H), 3.42 (m, 1H), 2.99 (m, 1H), 2.51 (m, 1H), 2.45 (q, 2H), 2.25 (td, 1H), 2.01 (m) , 4H), 1.86 (td, 1H), 1.70 (m, 2H), 1.56 (m, 2H), 1.17 (t, 3H)

Preparation 49: 4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

4-Chloro-2-fluoro-1-nitro-benzene (5.0 g, 28.2 mmol) was reacted according to the procedure of Preparations 1, 2, 3 and 7 to give the title compound (5.3 g, 4 steps total yield) The rate is 47%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (s, 2H), 6.85 (d, 1H), 6.82 (d, 1H), 6.71 (t, 1H), 4.31 (m, 1H), 4.18 (m, 2H) ), 3.61 (s, 2H), 3.52 (m, 2H), 3.39 (m, 1H), 2.66 (m, 1H), 2.49 (m, 1H), 2.23 (m, 1H), 2.05 (s, 3H) , 2.02 (m, 4H), 1.86 (m, 1H), 1.70 (m, 2H), 1.56 (m, 2H)

Preparation 50: 4-(1,4-Dioxa-spiro[4.5]dec-7-ene-8-yl)-2,5-difluoro-phenylamine

8-(2,5-Difluoro-4-nitro-phenyl)-1,4-dioxa-spiro[4.5]indole-7-ene (102 mg, 0.34 mmol) was dissolved in tetrahydrofuran (1 mL). Ethanol (1 mL) and water (1 mL). Iron (115 mg, 2.05 mmol) and ammonium chloride (110 mg, 2.05 mmol) were added sequentially, and the mixture was heated to 90 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered with a pad of celite and washed with ethyl acetate. The filtrate was distilled under reduced pressure, extracted with ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

NMR: ¹ H-NMR (CDCl ₃ ) 6.91 to 6.87 (1H, m), 6.46 to 6.41 (1H, m), 5.80 (1H, m), 4.01 (4H, s), 3.74 (2H, s), 2.57 (2H,m), 2.44 (2H,m), 1.88 (2H,m)

Preparation 51: 4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]cyclohexanecarboxylic acid ethyl ester

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (500 mg, 2.22 mmol) from Preparation Example 3 and ethyl 4-aminooxy-cyclohexanecarboxylate The ester (415 mg, 2.22 mmol

NMR: ¹ H-NMR (CDCl ₃ ) 6.81-6.75 (1H, m), 6.45 (1H, m), 4.22 (0.4H, m), 4.13 (2.6H, m), 3.97 (1H, m), 3.69 (2H, m), 3.37 (1H, m), 2.97 (1H, m), 2.47 (1H, m), 2.35~2.15 (4H, m), 1.96 (3H, m), 1.87~1.68 (3H, m ), 1.62~1.49(3H,m), 1.34(1H,m),1.25(3H,m)

Preparation 52: 4-[4-(4-Tertiaryoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneamino]cyclohexanecarboxylic acid ethyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]cyclohexanecarboxylic acid ethyl ester from Preparation 51 (880 mg, 2.23) Methyl) was dissolved in acetonitrile (50 mL). Boc ₂ O (489 mg, 2.23 mmol) and DMAP (27 mg, 0.223 mmol) were slowly added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals

NMR: ¹ H-NMR (CDCl ₃ ) 6.88 (2H, m), 4.25 (0.3H, m), 4.14 (2.7H, m), 3.98 (1H, m), 3.45 (1H, m), 3.08 (1H) , m), 2.51 (1H, m), 2.39~2.15 (3H, m), 2.04 (4H, m), 1.87~1.72 (3H, m), 1.56 (2H, m), 1.44 (1OH, m), 1.24(1H,m), 1.24(3H,m)

Preparation 53: 4-[4-(4-Tertiaryoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid

4-[4-(4-Terti-butoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid B, obtained from Preparation 52 The base ester (900 mg, 1.82 mmol) was dissolved in tetrahydrofuran / water / methanol (5 / 3 / 1) (10 mL). Lithium hydroxide (15 mg, 3.64 mmol) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture is distilled under reduced pressure to remove the solvent and subjected to column chromatography. The title compound (390 mg, 46% yield) was obtained. The obtained compound was used in the next reaction without further purification.

Quality (EI) 467 (M ⁺ +1)

Preparation 54: (2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]] Tert-butyl-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester

4-[4-(4-Terti-butoxycarbonylamino-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-cyclohexanecarboxylic acid from Preparation Example 53 390 mg, 0.836 mmol) was dissolved in dichloromethane (20 mL). N-Hydroxy-isopropyl hydrazine (102 mg, 1.00 mmol) and diisopropylcarbodiimide (0.157 mL, 1.00 mmol) were added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and evaporated. The mixture was again dissolved in dimethylformamide (10 mL) and stirred at 150 ° C for 3 hr. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals crystals

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, m), 6.86 (1H, m), 6.66 (1H, s), 4.05 (1H, m), 3.39 (1H, m), 3.10~3.01 (2H) , m), 2.92 (1H, m), 2.45 (1H, m), 2.22 (5H, m), 2.05 (2H, m), 1.90 (1H, m), 1.75 (2H, m), 1.59 (1H, m), 1.52~1.40 (12H, m), 1.32 (6H, d)

Preparation 55: (2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]] Tert-butyl-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester

The title compound (77 mg, 17% yield) was obtained according to the procedure of the procedure The obtained compound was used in the next reaction without further purification.

Quality (EI) 533 (M ⁺ +1)

Preparation 56: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[4-(3-isopropyl-[1,2,4] Diazol-5-yl)-cyclohexyl]-oxime

(2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]) from Preparation 55 The oxazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester (77 mg, 0.014 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and brine. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

NMR: ¹ H-NMR (CDCl ₃ ) 6.79 (1H, m), 6.45 (1H, m), 4.30 (1H, s), 3.70 (2H, s), 3.43 (1H, m), 3.05 (1H, m ), 2.96 (2H, m), 2.48 (1H, m), 2.23 (1H, m), 2.03 to 1.87 (9H, m), 1.72 (2H, m), 1.60 to 1.49 (2H, m), 1.33 ( 6H,d)

Preparation 57: 4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl ]-肟

4-Bromo-2,3-difluoro-phenylamine (3.02 g, 14.51 mmol) was obtained according to the procedure of Preparations 22, 1, 2, 3, and 7 to give the title compound (663 mg, 5 steps total) Yield 44%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, m), 6.72 to 6.69 (1H, m), 6.50 to 6.46 (1H, m), 4.31 (1H, m), 4.17 to 4.12 (2H, m) , 3.71 (2H, s), 3.54~3.41 (3H, m), 3.00 (1H, m), 2.57~2.45 (1H, m), 2.30~2.20 (1H, m), 2.10 (3H, s), 2.05 ~1.90(4H,m), 1.80~1.70(1H,m),1.75~1.65(24H,m),1.60~1.40(2H,m)

Preparation 58: 4-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

1-Chloro-2-fluoro-4-nitro-benzene (0.20 g, 1.14 mmol) was obtained according to the procedure of Preparations 1, 2, 3, 5 and 32 to give the title compound (0.15 g, 5 steps) The total yield is 34%).

NMR: ¹ H-NMR (CDCl ₃ ) 6.91 (1H, t), 6.39 (1H, d), 6.35 (1H, d), 4.91 (1H, m), 4.21 (1H, m), 3.68 (4H, s ), 3.39 (1H, m), 3.26 (2H, m), 2.96 (1H, t), 2.46 (1H, m), 2.22 (1H, m), 2.05~1.80 (5H, m), 1.70~1.50 ( 4H, m), 1.23 (6H, d)

Preparation 59: 4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-Chloro-2-fluoro-1-nitro-benzene (1.0 g, 5.63 mmol) was reacted according to the procedure of Preparations 1, 2, 3, 5 and 32 to give the title compound (0.78 g, 5 steps) The total yield is 35%).

NMR: ¹ H-NMR (CDCl ₃ ) 6.82 (1H, d), 6.75 (1H, d), 6.70 (1H, t), 4.90 (1H, m), 4.20 (1H, m), 3.69 (3H, s ), 3.55 (1H, s), 3.38 (1H, m), 3.26 (2H, m), 2.64 (1H, m), 2.46 (1H, m), 2.21 (1H, m), 2.02 (2H, m) , 1.95~1.80(3H,m), 1.70~1.45(4H,m),1.23(6H,d)

Preparation 60: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidine-4- Base]-肟

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester from Preparation Example 5. (0.17 g, 0.40 mmol) and 2-chloro-5-cyclopropyl-pyrimidine.

NMR: ¹ H-NMR (CDCl ₃ ) 8.10 (2H, s), 6.79 (1H, m), 6.46 (1H, m), 4.30 (1H, m), 4.15 (2H, m), 3.69 (2H, s ), 3.52 (2H, m), 3.43 (1H, d), 2.99 (1H, t), 2.51 (1H, d), 2.26 (1H, m), 2.00 (4H, m), 1.85 (2H, m) , 1.76~1.46(4H,m),0.89(2H,m),0.57(2H,m)

Preparation 61: 4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidine-4 -基]-肟

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester from Preparation Example 5. (0.35 g, 0.83 mmol) and 2-chloro-5-trifluoromethyl-pyrimidine.

NMR: ¹ H-NMR (CDCl ₃ ) 8.46 (2H, s), 6.77 (1H, m), 6.45 (1H, m), 4.33 (1H, m), 4.15 (2H, m), 3.74 (4H, m ), 3.42 (1H, m), 2.97 (1H, t), 2.52 (1H, d), 2.26 (1H, m), 2.01 (4H, m), 1.90 (1H, m), 1.80 (2H, m) , 1.60 (2H, m)

Preparation 62: 4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylene Aminooxy]-piperidine-1-carboxylic acid phenyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester from Preparation Example 5. (0.12 g, 0.28 mmol) and EtOAc (EtOAc)

NMR: ¹ H-NMR (CDCl ₃ ) 7.37 (2H, t), 7.18 (1H, t), 7.11 (2H, d), 6.78 (1H, m), 6.47 (1H, m), 4.30 (1H, m ), 3.86 (1H, s), 3.78 (1H, s), 3.70 (2H, s), 3.53 (1H, s), 3.48~3.38 (2H, m), 2.98 (1H, t), 2.52 (1H, d), 2.27 (1H, m), 2.08~1.95 (4H, m), 1.88 (1H, m), 1.78 (2H, s), 1.65~1.58 (2H, m)

Preparation 63: 3-[2-Fluoro-4-(4-oxocyclohexyl)phenyl]-1,1-dimethylurea

4-Chloro-2-fluoro-1-nitrobenzene was reacted in the same manner as in Preparations 1, 2 and 3 to synthesize 4-(4-amino-3-fluorophenyl)cyclohexanone. To the compound (0.223 g, 1 mmol) was added dichloromethane (20 mL). The reaction mixture was cooled to EtOAc (mjqqqqqq

NMR: ¹ H-NMR (CDCl ₃ ) 8.04 (1H, t), 6.99 (1H, d), 6.93 (1H, m), 6.48 (1H, brs), 3.05 (6H, s), 2.98 (1H, m ), 2.49 (4H, m), 2.19 (2H, m), 1.90 (2H, m), 1.25 (1H, m)

Preparation 64: 4-({4-[4-(dimethylaminocarbamimidino)-3-fluoro-phenyl]cyclohexylene}amino)oxypiperidine-1-carboxylic acid III Butyl ester

3-[2-Fluoro-4-(4-oxocyclohexyl)benzene obtained in Preparation Example 63 -1,1-dimethylurea (0.25 g, 0.9 mmol) and the 4-aminooxy-piperidine-1-carboxylic acid tert-butyl ester from Preparation 4 were the same according to Preparation 5 The title compound (0.41 g, 96% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.00 (1H, t), 6.94 (1H, m), 6.89 (1H, m), 6.46 (1H, m), 4.20 (1H, m), 3.68 (2H, m ), 3.41 (1H, m), 3.22 (2H, m), 3.04 (6H, s), 2.70 (1H, m), 2.49 (1H, m), 2.22 (1H, m), 2.02 (2H, m) , 1.87 (3H, m), 1.62 (5H, m), 1.45 (9H, s)

Preparation 65: 4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid tert-butyl ester

4-Chloro-2-fluoro-1-nitrobenzene was reacted in the same manner as in Preparations 1, 2 and 3 to synthesize 4-(4-amino-3-fluorophenyl)-cyclohexanone. The synthesized compound (0.452 g, 2.1 mmol) and the 4-aminooxy-piperidine-1-carboxylic acid tert-butyl ester from Preparation 4 were reacted in the same manner as in Preparation 5 to give the title compound. (0.8 g, 91% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 6.82 (2H, m), 6.73 (1H, m), 4.20 (1H, m), 3.65 (2H, brs), 3.39 (1H, m), 3.23 (2H, m ), 2.66 (1H, m), 2.47 (2H, m), 2.21 (1H, m), 2.00 (1H, m), 1.87 (4H, m), 1.63 (4H, m), 1.52 (4H, m)

Preparation 66: 4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid isopropyl ester

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid tert-butyl ester (0.8 g, obtained from Preparation 65) 2 mmol) was reacted in the same manner as in the title compound 32 to give the title compound (0.36 g, 47% yield rate).

NMR: ¹ H-NMR (CDCl ₃ ) 6.82 (1H, m), 6.76 (1H, m), 6.71 (1H, m), 4.90 (1H, m), 4.21. (1H, m), 3.69 (2H, brs ), 3.62 (2H, m), 3.39 (1H, m), 3.27 (2H, m), 2.65 (1H, m), 2.48 (1H, m), 2.20 (1H, m), 2.00 (2H, m) , 1.87 (3H, m), 1.60 (2H, m), 1.51 (2H, m), 1.23 (6H, d)

Preparation 67: 4-[4-(1,4-Dioxaspiro[4,5]nonane-8-yloxyimino)cyclohexyl]-2,5-difluoroaniline

4-(4-Amino-2,5-difluorophenyl)-cyclohexanone (0.13 g, 0.57 mmol) and O-(1,4-dioxaspiro[4.5] from Preparation Example 3. The decane-8-yl)hydroxylamine (0.098 g, 0.57 mmol.

NMR: ¹ H-NMR (CDCl ₃ ) 6.77 (1H, m), 6.45 (1H, m), 4.17 (1H, m), 3.95 (4H, s), 3.68 (2H, brs), 3.42 (1H, m ), 2.97 (1H, m), 2.50 (1H, m), 2.23 (1H, m), 2.00 (1H, m), 1.85 (8H, m), 1.60 (3H, m), 1.50 (1H, m)

Preparation 68: 4-{[4-(4-Amino-2,5-difluorophenyl)cyclohexylene]amino}oxycyclohexanone

Tetrahydrofuran (7.3 mL) was added to 4-[4-(1,4-dioxaspiro[4,5]nonane-8-yloxyimino)cyclohexyl]-2,5 from Preparation 67. -Difluoroaniline (0.2 g, 0.5 mmol) was neutralized and cooled to 0 °C. A 6 N aqueous HCl solution (1.5 mL) was slowly added dropwise to the mixture, and the mixture was stirred at room temperature. After the completion of the reaction was confirmed by TLC, it was adjusted to pH 7 using aqueous sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic layer is dehydrated with anhydrous magnesium sulfate, filtered and decompressed. Distillation gave the title compound (0.18 g,j.

NMR: ¹ H-NMR (CDCl ₃ ) 6.78 (1H, m), 6.46 (1H, m), 4.43 (1H, m), 3.71 (2H, brs), 3.43 (1H, m), 2.99 (1H, m ), 2.50 (4H, m), 2.20 (5H, m), 1.88 (3H, m), 1.60 (3H, m)

Preparation 69: 4-[4-(4-Tertiaryoxyiminocyclohexyloxy)iminocyclohexyl]2,5-difluoroaniline

4-{[4-(4-Amino-2,5-difluorophenyl)cyclohexylene]amino}oxycyclohexanone (0.18 g, 0.5 mmol) from Preparation 68 and O- The third butylhydroxylamine hydrochloride (0.06 g, 0.5 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 6.73 (1H, m), 6.45 (1H, m), 4.28 (1H, m), 3.69 (2H, brs), 3.42 (1H, m), 2.97 (1H, m ), 2.65 (1H, m), 2.49 (1H, m), 2.42 (2H, m), 2.22 (2H, m), 1.96 (7H, m) 1.57 (2H, m), 1.27 (9H, m)

Preparation 70: 4-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester

1-Chloro-2-fluoro-4-nitro-benzene (0.5 g, 2.9 mmol) was reacted in the same manner as in Preparations 1, 2 and 3 to give 4-(4-amino-2-fluoro-benzene Base)-cyclohexanone. The title compound (0.25 g, 21% yield) was obtained from m.

NMR: ¹ H-NMR (CDCl ₃ ) 7.37 (2H, t), 7.18 (1H, t), 7.11 (2H, d), 6.92 (1H, t), 6.39 (2H, m), 4.30 (1H, m ), 3.86 (1H, s), 3.78 (1H, s), 3.70 (2H, s), 3.54 (1H, s), 3.44 (2H, m), 2.98 (1H, t), 2.52 (1H, d) , 2.27 (1H, m), 2.04 (4H, m), 1.88 (1H, m), 1.78 (2H, s), 1.60 (2H, m)

Preparation 71: 4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester

4-Chloro-2-fluoro-1-nitrobenzene (0.5 g, 2.9 mmol) was reacted in the same manner as in Preparations 1, 2 and 3 to give 4-(4-amino-3-fluoro-phenyl). )-cyclohexanone. The title compound (0.32 g, 26% yield) was obtained from m.

NMR: ¹ H-NMR (CDCl ₃ ) 7.37 (2H, t), 7.18 (1H, t), 7.11 (2H, d), 6.82 (1H, d), 6.75 (1H, d), 6.68 (1H, t ), 4.31 (1H, m), 3.86 (1H, s), 3.78 (1H, s), 3.71 (2H, s), 3.54 (1H, s), 3.43 (2H, m), 2.98 (1H, t) , 2.52 (1H, d), 2.27 (1H, m), 2.06 (4H, m), 1.90 (1H, m), 1.77 (2H, s), 1.65~1.50 (2H, m)

Preparation 72: 4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yl]-indole

4-Chloro-2-fluoro-1-nitrobenzene was reacted in the same manner as in Preparations 1, 2 and 3 to synthesize 4-(4-amino-3-fluorophenyl)-cyclohexanone. The synthesized compound was obtained from O-[1-(3-isopropyl-[1,2,4] obtained in Preparation Example 11. The oxazol-5-yl)-piperidin-4-yl]-hydroxylamine (1.1 g, 4.8 mmol).

NMR: ¹ H-NMR (CDCl ₃ ) 6.85 (1H, d), 6.77 (1H, d), 6.70 (1H, t), 4.32 (1H, m), 3.80 (4H, m), 3.53 (2H, m) ), 3.41 (1H, m), 2.96 (1H, t), 2.92 (1H, m), 2.52 (1H, m), 2.28 (1H, m), 2.05 (4H, m), 1.90 (3H, m) , 1.61 (2H, m), 1.28 (6H, d)

Preparation 73: 3-Aminooxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester

3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.31 g, 0.14 mmol) was reacted in the same manner as in Preparations 14, 32 and 15 to give The title compound (127 mg, 35% yield).

¹ H-NMR (CDCl ₃ ) 7.36 (2H, t), 7.17 (1H, t), 7.13 (2H, d), 5.27 (2H, s), 4.40 (1H, s), 4.30 (1H, s), 3.86 (1H, s), 2.20~1.95 (8H, m)

Preparation 74: 3-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneamino]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid Phenyl ester

1-Chloro-2-fluoro-4-nitro-benzene was reacted in the same manner as in Preparations 1, 2 and 3 to synthesize 4-(4-amino-2-fluorophenyl)-cyclohexanone. The synthesized compound and 3-aminooxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester (127 mg, 0.48 mmol) from Preparation 73 were obtained according to Preparation 12. The title compound (201 mg, 92% yield).

¹ H-NMR (CDCl ₃ ) 7.37 (2H, t), 7.18 (1H, t), 7.14 (2H, d), 6.96 (1H, t), 6.39 (2H, m), 4.44 (2H, s), 4.35 (1H, s), 3.68 (2H, s), 3.36 (1H, d), 3.00 (1H, t), 2.54 (1H, d), 2.30 to 1.90 (12H, m), 1.68 (2H, m)

Preparation 75: 4-Aminooxymethyl-piperidine-1-carboxylic acid tert-butyl ester

Take piperidin-4-yl-methanol (15.4g, 133.7mmol) and di-dicarbonate The title compound (2.52 g, 90% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 5.36 (2H, s), 4.09~4.07 (2H, m), 3.52 (2H, d), 2.69 (2H, m), 1.80 (1H, m), 1.68 (2H) , m), 1.46 (9H, s), 1.11 (2H, m)

Preparation 76: 4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone (0.58 g, 2.61 mmol) from Preparation Example 3 and 4-aminooxymethyl group from Preparation 75 The butyl-piperidine-l-carboxylic acid tert-butyl ester (0.60 g, 2.61 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 6.78-6.73 (1H, m), 6.48-6.40 (1H, m), 4.19 (2H, m), 3.90 (2H, d), 3.80 (2H, s), 3.41 ~3.40(1H,m), 3.00(1H,m), 2.80(2H,m), 2.49~2.46(2H,m),2.35~2.22(1H,m),2.00~1.80(6H,m),1.70 ~1.58(1H,m), 1.46(9H,s), 1.45~1.43(2H,m)

Example 1: 4-(4-{2,5-Difluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexyleneaminooxy - piperidine-1-carboxylic acid tert-butyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester from Preparation Example 5. (33mg, 0.078 mmol) was dissolved in dichloromethane (2 mL). EtOAc (EtOAc, m. 3-Hydroxyazetidine hydrochloride (9.3 mg, 0.0857 mmol) and triethylamine (78 mg, 0.58 mmol) were added, and stirred at room temperature for 10 min. After the reaction was quenched with water, the mixture was washed with dichloromethane, water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

NMR: ¹ H-NMR (CDCl ₃ ) 7.92 to 7.90 (1H, m), 6.86 to 6.84 (1H, m), 6.12 (1H, s), 4.71 (1H, m), 4.35 to 4.25 (2H, m) , 4.20 (1H, m), 4.00~3.90 (2H, m), 3.72~3.60 (2H, m), 3.45~3.40 (1H, m), 3.30~3.15 (2H, m), 3.03 (1H, m) , 2.57 (1H, d), 2.55~2.57 (1H, m), 2.23 (1H, m), 2.10~1.90 (2H, m), 1.90~1.80 (3H, m), 1.55~1.17 (4H, m) , 1.46 (9H, s)

Example 2: 4-(4-{2,5-Difluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexyleneaminooxy )-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Preparation Example 32 ( The title compound (38 mg, 61% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.94 to 7.90 (1H, m), 6.87 to 6.82 (1H, m), 6.12 (1H, s), 4.94 to 4.88 (1H, m), 4.72 (1H, s) , 4.30 (2H, t), 4.23~4.18 (1H, m), 3.98~3.94 (2H, m), 3.73~3.67 (2H, m), 3.42~3.38 (1H, m), 3.31~3.22 (2H, m), 3.04 (1H, t), 2.52 (1H, d), 2.36 (1H, s), 2.28~2.22 (1H, m), 2.06~1.94 (2H, m), 1.92~1.82 (3H, m) , 1.70~1.45(4H,m),1.25(6H,d)

Example 3: 3-Hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-guanamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl]-indole (25.7 mg, 0.056 mmol)yyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyy .

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.95 to 7.90 (1H, m), 6.88 to 6.84 (1H, m), 6.12 (1H, s), 4.71 (1H, m), 4.35 ~4.22(3H,m), 4.22~4.10(2H,m), 4.00~3.90(2H,m), 3.60~3.40(3H,m),3.04(1H,m),2.52(1H,d),2.32 ~2.20(2H,m), 2.11(3H,s), 2.10~1.95(4H,m), 1.90~1.80(1H,m),1.78~1.60(2H,m),1.50~1.40(2H,m)

Example 4: 3-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro- Phenyl)-1,1-dimethyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-yl]-indole (40 mg, 0.09 mmol), dimethylamine hydrochloride (8.1 mg, 0.18 mmol), pyridine (5 μl, 0.07 mmol), diisopropylethylamine (94 μl, 0.54 mmol) The reaction of the title compound (10 mg, 22% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ): 8.22 (2H, s), 7.96-7.91 (1H, m), 6.88-6.65 (1H, m), 6.58 (1H, s), 4.31 (1H, m), 4.19-4.13(2H,m), 3.55-3.53(2H,m), 3.52-3.50(1H,m),3.03(6H,m),2.51-2.43(3H,m),2.27-2.26(2H,m ), 2.03-2.01 (4H, m), 1.99 (1H, m), 1.72-1.30 (4H, m), 1.20-1.17 (3H, m)

Example 5: 3-Hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino] -cyclohexyl}-2,5-difluoro-phenyl)-decylamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-based]-肟 (12mg, 0.028 mmol), 3-hydroxyazetidine (6 mg, 0.056 mmol), diisopropylethylamine (10 μl, 0.056 mmol) and triphosgene (8 mg, 0.028 mmol) were reacted in the same manner as in Example 1. The title compound (11.9 mg, 80% yield).

NMR: ¹ H-NMR (CDCl ₃ ): 8.16 (2H, s), 7.92-7.89 (1H, m), 6.87-6.84 (1H, m), 6.13 (1H, s), 4.70 (1H, m), 4.31-4.27(3H,m), 4.20-4.00(2H,m),3.77~3.71(2H,m),3.53-3.50(3H,m),3.10-3.03(1H,m),2.85(1H,m ), 2.45 (3H, m), 2.25 (1H, m), 2.01 (4H, m), 1.87 (1H, m), 1.71 (2H, m), 1.68 (2H, m), 1.17 (3H, m)

Example 6: 4-cyclopropyl-per pipe 1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-guanamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-yl]-indole (26 mg, 0.057 mmol) with 1-cyclopropyl-per pipe The hydrochloride (14 mg, EtOAc, m.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.92 to 7.87 (1H, m), 6.89 to 6.84 (1H, m), 6.55 (1H, s), 4.30 (1H, m), 4.20 ~4.09(2H,m), 3.58~3.40(7H,m),3.04(1H,m),3.80~3.70(4H,m),2.52(1H,d),2.32~2.20(2H,m),2.11 (3H, s), 2.10~ 1.95(4H,m), 1.90~1.80(1H,m), 1.78~1.60(3H,m), 1.50~1.40(1H,m),0.50~0.40(4H,m)

Example 7: (4-{4-[1-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea

4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl] from Preparation 27 -肟(51mg, 0.122mmol) and ammonia solution (0.5M 1,4-two The title compound (41 mg, 73% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 8.21 (2H, s), 7.18 - 7.08 (2H, m), 6.96 - 6.93 (1H, m), 6.47 (1H, s), 4.67 (2H, s), 4.30 (1H,m), 4.15~4.05(2H,m), 3.60~3.40(3H,m),3.05(1H,m),2.55(1H,m),2.35~2.25(1H,m),2.10~1.90 (4H,m), 1.95~1.85(1H,m), 1.78~1.60(2H,m), 1.50~1.40(2H,m)

Example 8: 4-[4-(2,5-Difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester

4-[4-(2,5-Difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl group from Example 10 The ester (110 mg, 0.243 mmol) was dissolved in tetrahydrofuran (3 mL). Chlorobutyl chloride (50 mg, 0.364 mmol) and triethylamine (36 mg, 0.364 mmol) were stirred at room temperature for 10 min. After the solid was filtered off, sodium borohydride (492 mg, 13.01 mmol) was added, dissolved in water (0 ° C) and stirred at room temperature for 3 hr. After the reaction was quenched by the addition of 1N aqueous hydrochloric acid, the mixture was washed with ethyl acetate, water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous MgSO.sub.

NMR: ¹ H-NMR (CDCl ₃ ) 7.12 to 7.10 (1H, m), 6.89 to 6.85 (1H, m), 4.72 (2H, d), 4.23 (1H, m), 3.70 to 3.60 (2H, m) , 3.50~3.40(1H,m), 3.25~3.15(2H,m), 3.09(1H,m), 2.60~2.50(1H,m), 2.30~2.20(1H,m),2.10~2.00(2H, m), 1.95~1.80(3H,m), 1.70~1.60(4H,m), 1.46(9H,s)

Example 9: 4-[4-(2,5-Difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-[4-(2,5-Difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester from Example 8. (85 mg, 0.193 mmol.

NMR: ¹ H-NMR (CDCl ₃ ) 7.12 to 7.10 (1H, m), 6.89 to 6.85 (1H, m), 4.92 (1H, m), 4.72 (2H, d), 4.23 (1H, m), 3.80 ~3.70 (2H,m), 3.50~3.40(1H,m), 3.30~3.20(2H,m),3.09(1H,m), 2.60~2.50(1H,m), 2.30~2.20(1H,m) , 2.10~2.00(2H,m), 1.95~1.80(3H,m), 1.70~1.60(4H,m),1.24(6H,d)

Example 10: 4-[4-(2,5-Difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester

The 2,5-difluoro-4-(4-o-oxy-cyclohexyl)-benzoic acid methyl ester (71 mg, 0.264 mmol) from Preparation 35 was reacted in the same manner as in Preparation 5 to give the title compound. (115 mg, 93% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 7.61 to 7.52 (1H, m), 6.99 to 6.95 (1H, m), 4.22 (1H, m), 3.92 (3H, s), 3.75 to 3.65 (2H, m) , 3.50~3.40(1H,m), 3.30~3.20(2H,m), 3.09(1H,m), 2.60~2.50(1H,m), 2.30~2.20(1H,m),2.10~2.00(2H, m), 1.95~1.80(3H,m), 1.70~1.60(4H,m), 1.46(9H,s)

Example 11: (2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl )-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-yl]-oxime (50 mg, 0.11 mmol) and ammonium chloride (9 mg, 0.16 mmol) in the same manner as in Example 1. Reaction gave the title compound (30 mg, 54% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.87 to 7.83 (1H, m), 7.00 to 6.86 (1H, m), 6.49 (1H, s), 4.63 (2H, s), 4.30 (1H,m), 4.20~4.10(2H,m), 3.60~3.40(3H,m),3.04(1H,m),2.52(1H,m),2.32~2.20(1H,m),2.11(3H , s), 2.10~1.95(4H,m), 1.90~1.80(1H,m), 1.78~1.60(2H,m), 1.50~1.40(2H,m)

Example 12: 3-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-1,1-dimethyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Mexyl]-indole (50 mg, 0.11 mmol), m.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.96 to 7.91 (1H, m), 6.88 to 6.84 (1H, m), 6.53 (1H, s), 4.30 (1H, m), 4.20 ~4.10(2H,m), 3.58~3.40(3H,m), 3.10~3.00(7H,m),2.52(1H,m),2.32~2.20(1H,m),2.11(3H,s),2.10 ~1.95(4H,m), 1.90~1.80(1H,m),1.78~1.60(2H,m),1.50~1.40(2H,m)

Example 13: 4-[4-(2,5-Difluoro-4-{[(3-hydroxy-azetidin-1-carbonyl)-amino]-methyl}-phenyl)-cyclo ring Hexylaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Aminomethyl-2,5-difluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl group obtained in Preparation Example 42 Ester (88 mg, 0.21 mmol), diisopropylethylamine (74 μl, 0.42 mmol), triphosgene (62 mg, 0.21 mmol) and 3-hydroxyazetidine (46 mg, 0.42 mmol) The title compound was obtained (15 mg, 14% yield).

NMR: ¹ H-NMR (CDCl ₃ ): 7.07-7.02 (1H, m), 6.87-6.83 (1H, m), 4.92-4.89 (1H, m), 4.62-4.59 (2H, m), 4.36 (2H) , d), 4.23-4.13 (3H, m), 3.85-3.82 (2H, m), 3.71 (2H, m), 3.40 (1H, d), 3.29-3.25 (2H, m), 3.10 (1H, t ), 2.50 (1H, d), 2.25 (1H, m), 2.05 (2H, m), 1.95-1.78 (5H, m), 1.67-1.64 (3H, m), 1.23 (6H, d)

Example 14: 4-[4-(2,5-Difluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Preparation Example 32 ( 113mg, 0.275 Methyl acetate (22 mg, 0.41 mmol

NMR: ¹ H-NMR (CDCl ₃ ) 7.90 to 7.86 (1H, m), 6.88 to 6.84 (1H, m), 4.92 (1H, m), 4.84 (2H, m), 4.21. (1H, m), 3.78 ~3.60(2H,m), 3.44~3.41(1H,m), 3.30~3.20(2H,m), 3.00(1H,m), 2.50~2.40(1H,m),2.30~2.20(1H,m) , 2.10~1.90(2H,m), 1.90~1.80(3H,m),1.65~1.45(4H,m),1.23(6H,d)

Example 15: 4-{4-[2,5-Difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl Base ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Preparation Example 32 ( Reaction with propylamine (18 mg, 0.18 mmol

NMR: ¹ H-NMR (CDCl ₃ ) 7.99 to 7.89 (1H, m), 7.17 (1H, s), 6.83 to 6.79 (1H, m), 5.60 (1H, s), 4.90 (1H, m), 4.20 (1H,m), 3.72~3.62(2H,m), 3.41~3.38(1H,m),3.35~3.18(4H,m), 3.00(1H,m),2.50~2.40(1H,m),2.30 ~2.20(1H,m), 2.10~1.90(2H,m), 1.90~1.80(3H,m),1.70~1.40(6H,m),1.23(6H,d),0.93(3H,t)

Example 16: 4-{4-[2,5-Difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid Propyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Preparation Example 32 ( Reaction of the title compound (32 mg, 86% yield)

NMR: ¹ H-NMR (CDCl ₃ ) 7.91 to 7.87 (1H, m), 6.87 to 6.82 (1H, m), 6.28 (1H, s), 4.92 (1H, m), 4.45 (1H, d), 4.20 (1H,m), 4.00(1H,m), 3.78~3.68(2H,m), 3.44~3.41(1H,m), 3.30~3.20(2H,m),3.07(1H,m),2.55~2.45 (1H,m), 2.35~2.25(1H,m), 2.10~1.88(5H,m),1.75~1.60(4H,m),1.30~1.15(12H,m)

Example 17: 4-(4-{2,5-Difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneamino)-piperidine- 1-carboxylic acid isopropyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Preparation Example 32 ( The title compound (22 mg, 59% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 7.87 to 7.83 (1H, m), 6.88 to 6.84 (1H, m), 6.71 (1H, s), 5.13 (1H, m), 4.92 (1H, m), 4.22 (1H,m), 3.85~3.62(4H,m), 3.49~3.38(3H,m), 3.30~3.20(2H,m),3.07(1H,m),2.55~2.45(1H,m),2.32 ~2.20(2H,m), 2.10~1.88(5H,m), 1.70~1.60(4H,m),1.23(6H,d)

Example 18: 4-(4-{4-[3-(2,3-Dihydroxy-propyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneaminooxy)- Piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Preparation Example 32 ( The title compound (24 mg, 61% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.85 to 7.80 (1H, m), 6.89 to 6.85 (1H, m), 6.70 (1H, s), 5.22 (1H, m), 4.91 (1H, m), 4.22 (1H, m), 3.90 (1H, m), 3.80~3.62 (4H, m), 3.51~3.40 (3H, m), 3.30~3.20 (2H, m), 3.07 (1H, m), 2.55~2.45 (1H,m), 2.30~2.20(1H,m), 2.10~1.88(5H,m), 1.70~1.60(4H,m),1.23(6H,d)

Example 19: 4-[4-(4-Methanesulfonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester

1-Chloro-4-methylsulfonyl-benzene (228 mg, 1.197 mmol) was obtained according to the procedure of Preparations 1, 2, 3, and 5 to give the title compound (80 mg, 4 .

NMR: ¹ H-NMR (CDCl ₃ ) 7.89 to 7.87 (2H, m), 7.42 to 7.40 (2H, m), 4.22 (1H, m), 3.71 to 3.61 (2H, m), 3.50 to 3.40 (1H, m), 3.28~3.18(2H,m), 3.08(3H,s), 2.90~2.80(1H,m), 2.60~2.50(1H,m), 2.30~2.20(1H,m),2.18~2.05( 2H,m), 1.95~1.83(3H,m), 1.78~1.60(4H,m), 1.46(9H,s)

Example 20: 4-(4-{4-[(3-Hydroxy-azetidin-1-yl)-amino]-phenyl}-cyclohexyleneamino)-piperidin-1- Tert-butyl carboxylate

4-[4-(4-Amino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (18 mg, 0.05 mmol) from Preparation 31 3-Hydroxyazetidine hydrochloride (8 mg, 0.06 mmol)yield

NMR: ¹ H-NMR (CDCl ₃ ) 7.56~7.31 (2H, m), 7.17~7.14 (2H, m), 6.09 (1H, s), 4.67 (1H, m), 4.30~4.20 (3H, m) , 4.00~3.90(2H,m), 3.75~3.65(2H,m), 3.49~3.39(1H,m), 3.30~3.15(2H,m),2.76(1H,m),2.55~2.47(1H, m), 2.33~2.22(1H,m), 2.10~1.90(2H,m), 1.90~1.80(4H,m),1.55~1.17(4H,m),1.46(9H,s)

Example 21: 4-(4-{4-[(3-Hydroxy-azetidin-1-yl)-amino]-phenyl}-cyclohexylideneamino)-piperidin-1- Isopropyl carboxylate

4-[4-(4-Amino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester (50 mg) from Preparation 31 according to Preparation 32 In the same manner as the reaction, 4-[4-(4-amino-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester was synthesized. The compound which was synthesized and the 3-hydroxyazetidine hydrochloride were reacted in the same manner as in Example 1 to give the title compound (37 mg,

NMR: ¹ H-NMR (CDCl ₃ ) 7.52~7.26 (2H, m), 7.13~7.11 (2H, m), 5.91 (1H, s), 4.91 (1H, m), 4.69 (1H, m), 4.30 ~4.18(3H,m),3.95~3.88(2H,m),3.79~3.67(2H,m), 3.41~3.37(1H,m),3.30~3.15(2H,m),2.73(1H,m) , 2.55~2.47(1H,m), 2.30~2.18(2H,m), 2.10~1.90(2H,m),1.90~1.80(3H,m),1.55~1.17(4H,m),1.14(6H, d)

Example 22: 3-Hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino) -cyclohexyl}-phenyl)-guanamine

4-(4-Amino-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime (obtained from Preparation Example 30) The title compound (20 mg, 80% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.52~7.26 (2H, m), 7.13~7.11 (2H, m), 5.90 (1H, s), 4.70 (1H, m), 4.34 ~4.25(3H,m), 4.21~4.10(2H,m),3.95~3.90(2H,m),3.65~3.40(3H,m),2.71(1H,m),2.52(1H,d),2.30 ~2.20(1H,m),2.10(3H,s), 2.10~1.94(4H,m), 1.90~1.80(1H,m),1.78~1.60(2H,m),1.50~1.40(2H,m)

Example 23: 3-Hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4]] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation Example 12. The oxazol-5-yl)-piperidin-4-yl]-indole (10 mg, 0.02 mmol) was reacted with 3-hydroxyazetidine hydrochloride in the same manner as in Example 1 to give the title compound (10 mg, 81 %Yield).

NMR: ¹ H-NMR (CDCl ₃ ) 7.92 to 7.88 (1H, m), 7.89 to 7.83 (1H, m), 6.14 (1H, s), 4.70 (1H, s), 4.32 to 4.28 (3H, m) , 3.99~3.94(2H,m), 3.80~3.73(2H,m), 3.55~3.48(2H,m), 3.45~3.37(1H,m),3.03(1H,t),2.92~2.84(1H, m), 2.77 (1H, s), 2.52 (1H, d), 2.28~2.22 (1H, m), 2.08~1.92 (4H, m), 1.91~1.78 (3H, m), 1.68~1.45 (2H, m), 1.25 (6H, d)

Example 24: 1-(2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation Example 12. The oxazol-5-yl)-piperidin-4-yl]-indole (10 mg, 0.02 mmol) was obtained from the title compound (9 mg, 75% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 7.88 to 7.82 (1H, m), 7.92 to 7.82 (2H, m), 5.29 (1H, s), 4.32 to 4.28 (1H, m), 3.82 to 3.75 (4H, m), 3.54~3.47(2H,m), 3.47~3.38(3H,m),3.04(1H,t),2.92~2.85(1H,m),2.52(1H,s),2.28~2.22(1H, m), 2.08~1.94(4H,m), 1.92~1.79(3H,m), 1.68~1.47(2H,m),1.28(6H,d)

Example 25: (2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation Example 12. Diazol-5-yl)-piperidin-4-yl]-indole (10 mg, 0.02 mmol) and ammonia solution (0.5 M 1,4-two The title compound (5 mg, 45% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.88 to 7.82 (1H, m), 7.89 to 7.80 (2H, m), 4.86 (2H, s), 4.32 to 4.27 (1H, m), 3.82 to 3.75 (2H, m), 3.54~3.47(2H,m), 3.42(1H,d),3.04(1H,t),2.92~2.85(1H,m),2.52(1H,s),2.29~2.22(1H,m) , 2.08~1.95(4H,m), 1.93~1.78(3H,m),1.68~1.47(2H,m),1.28(6H,d)

Example 26: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl-indole (21 mg, 0.05 mmol) was obtained from the title compound (10 mg, 38% yield). rate).

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.82 to 7.78 (1H, m), 6.87 to 6.83 (1H, m), 6.46 (1H, s), 4.73 (1H, m), 4.29 (1H,m), 4.18~4.10(2H,m),3.87(1H,t),3.65(2H,d),3.52~3.40(3H,m),3.05(1H,m),2.52(1H,m ), 2.25 (1H, m), 2.10 (3H, s), 2.10~1.90 (4H, m), 1.90~1.80 (1H, m), 1.72~1.60 (2H, m), 1.50~1.40 (2H, m ), 1.33 (6H, s)

Example 27: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Methoxy]-indole (21 mg, 0.05 mmol

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.82 to 7.78 (1H, m), 6.87 to 6.83 (1H, m), 6.76 (1H, s), 5.00 (1H, m), 4.30 (1H,m), 4.20~4.10(2H,m), 3.97~3.90(1H,m), 3.52~3.40(4H,m), 3.20~3.10(1H,m),3.05(1H,m),2.52 (1H, m), 2.25 (1H, m), 2.10 (3H, s), 2.04 (1H, d), 2.10~1.90 (4H, m), 1.90~1.80 (1H, m), 1.72~1.60 (2H , m), 1.50~1.40 (2H, m), 1.22 (3H, d)

Example 28: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-ethyl)- Urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl-indole (20 mg, 0.048 mmol) was obtained from the title compound (14.6 mg, 60% yield).

^{1 H-NMR (400MHz, CDCl} 3); δ 8.20 (s, 2H), 7.88 (dd, 1H), 6.91 (dd, 1H), 6.76 (br s, 1H), 5.18 (t, 1H), 4.34 ( m,1H), 4.20 (m, 2H), 3.84 (m, 2H), 3.56 (m, 2H), 3.50 (m, 3H), 3.09 (t, 1H), 2.57 (d, 1H), 2.31 (m) , 2H), 2.16 (s, 3H), 2.04 (m, 4H), 1.95 (td, 1H), 1.74 (m, 2H), 1.60 (m, 2H)

Example 29: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl]-indole (20 mg, 0.048 mmol) was obtained eluted eluted eluted elute

^{1 H-NMR (500MHz, CDCl} 3); δ 8.16 (s, 2H), 7.83 (dd, 1H), 6.85 (dd, 1H), 6.47 (br s, 1H), 5.02 (t, 1H), 4.29 ( m,1H), 4.14 (m, 2H), 3.72 (m, 2H), 3.50 (m, 2H), 3.44 (m, 3H), 3.04 (t, 1H), 2.73 (m, 1H), 2.52 (d) , 1H), 2.26 (td, 1H), 2.11 (s, 3H), 1.99 (m, 4H), 1.87 (td, 1H), 1.73 (m, 4H), 1.55 (m, 2H)

Example 30: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-1-hydroxymethyl-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl]-indole (30 mg, 0.07 mmol) was obtained from the title compound (5 mg, 13% yield).

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.84 to 7.80 (1H, m), 7.21 (1H, s), 6.84 to 6.78 (1H, m), 6.12 (1H, d), 4.32 ~4.25(1H,m), 4.18~4.10(2H,m),3.92~3.78(5H,m),3.53~3.47(2H,m),3.43(1H,d),3.02(1H,t),2.52 (1H,d), 2.29~2.21(1H,m),2.10(3H,s),2.05~1.92(4H,m),1.91~1.82(1H,m),1.72~1.50(6H,m)

Example 31:1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl) -piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2,3-dihydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl-indole (30 mg, 0.07 mmol) was obtained from the title compound (yield:

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.82 to 7.78 (1H, m), 7.05 (1H, s), 6.88 to 6.80 (1H, m), 5.86 (1H, d), 4.32 ~4.27(1H,m),4.18~4.12(2H,m),3.94~3.50(4H,m),3.52~3.46(3H,m),3.43(1H,d),3.06(1H,t),2.53 (1H,d), 2.29~2.21(1H,m),2.10(3H,s),2.06~1.94(4H,m),1.91~1.82(1H,m),1.72~1.50(4H,m)

Example 32: N-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-methanesulfonamide

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Base]-indole (20 mg, 0.048 mmol) was dissolved in dichloromethane (4 mL). Diisopropylethylamine (40 mg, 0.31 mmol) and methanesulfonium chloride (30 mg, 0.31 mmol) were added and stirred. The compound was 18 hours. The reaction mixture was evaporated under reduced pressure to remove solvent, and then purified by Prep-TLC to give N-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine- 4-Methoxyimino]-cyclohexyl}-phenyl)-N-(methylsulfonyl)methanesulfonamide (18.3 mg, 67% yield).

The obtained N-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzene -N-(Methanesulfonyl)methanesulfonamide (17.3 mg, 0.030 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) were added, and calcium hydroxide (20 mg, 0.36 mmol) was added. ). The mixture was then stirred for 1 hour. The organic matter was extracted with water (20 mL) and ethyl acetate (20 mL). The residue was purified by EtOAc (EtOAc)

^{1 H-NMR (400MHz, CDCl} 3); δ 8.20 (s, 2H), 7.35 (dd, 1H), 7.02 (dd, 1H), 6.51 (br s, 1H), 4.35 (m, 1H), 4.20 ( m, 2H), 3.53 (m, 3H), 3.13 (m, 1H), 3.09 (s, 3H), 2.59 (d, 1H), 2.32 (td, 1H), 2.16 (s, 3H), 2.02 (m) , 4H), 1.92 (td, 1H), 1.73 (m, 2H), 1.61 (m, 2H)

Example 33: 1-(3-Fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl) -3-(2-hydroxy-ethyl)-urea

4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation Example 10. ]-肟(53mg, 0.133 The title compound (59 mg, 92% yield) was obtained from m.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.18 - 7.08 (2H, m), 6.95 - 6.93 (1H, m), 6.46 (1H, s), 5.04 (1H, m), 4.30 (1H,m), 4.20~4.10(2H,m),3.75~3.65(2H,m),3.55~3.40(5H,m),3.05(1H,m),2.55(1H,m),2.45~2.40 (1H, m), 2.25 (1H, m), 2.11 (3H, s), 2.10~1.95 (4H, m), 1.90~1.80 (1H, m), 1.78~1.60 (2H, m), 1.50~1.40 (2H,m)

Example 34: (3-Fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea

4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl] from Preparation 10 -肟(50mg, 0.131mmol) and ammonia solution (0.5M of 1,4-two The title compound (47 mg, 81% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.18 - 7.08 (2H, m), 6.95 - 6.93 (1H, m), 6.35 (1H, s), 4.62 (2H, s), 4.31 (1H,m), 4.20~4.10(2H,m), 3.56~3.40(3H,m),3.05(1H,m),2.55(1H,m),2.35~2.25(1H,m),2.11(3H , s), 2.05~1.90 (4H, m), 1.90~1.80 (1H, m), 1.78~1.60 (2H, m), 1.50~1.40 (2H, m)

Example 35: 3-Hydroxy-azetidine-1-carboxylic acid (3-fluoro-4-{4-[1- (5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine

4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation Example 10. - 肟 (50 mg, 0.131 mmol) and 3-hydroxyazetidine hydrochloride (22 mg).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.28 (1H, m), 7.09~7.07 (1H, m), 7.00 to 6.95 (1H, m), 5.94 (1H, s), 4.71 (1H,m), 4.32~4.22(3H,m),4.19~4.10(2H,m),3.98~3.90(2H,m),3.56~3.40(3H,m),3.05(1H,m),2.55 (1H,m), 2.20~2.20(1H,m),2.11(3H,s),2.08~1.95(4H,m),1.90~1.80(1H,m),1.78~1.60(2H,m), 1.50 ~1.40(2H,m)

Example 36: 1-(2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation Example 12. The oxazol-5-yl)-piperidin-4-yl]-indole (23 mg, 0.053 mmol), m. 23.0 mg, 81% yield).

^{1 H-NMR (400MHz, CDCl} 3); δ 7.92 (dd, 1H), 7.47 (br s, 1H), 6.86 (dd, 1H), 5.67 (br s, 1H), 4.33 (m, 1H), 3.82 (m, 2H), 3.56 (m, 4H), 3.48 (m, 3H), 3.43 (s, 3H), 3.07 (t, 1H), 2.93 (m, 1H), 2.54 (d, 1H), 2.29 ( Td, 1H), 2.05 (m, 4H), 1.85 (m, 3H), 1.56 (m, 2H), 1.32 (d, 6H)

Example 37: 1-(2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation Example 12. The oxazol-5-yl)-piperidin-4-yl]-indole (22 mg, 0.051 mmol) was obtained from the title compound (m. 19.0 mg, 68% yield).

^{1 H-NMR (400MHz, CDCl} 3); δ 7.93 (dd, 1H), 7.45 (br s, 1H), 6.86 (dd, 1H), 5.69 (br s, 1H), 4.33 (m, 1H), 3.81 (m, 2H), 3.59 (m, 6H), 3.48 (m, 3H), 3.07 (t, 1H), 2.92 (m, 1H), 2.54 (d, 1H), 2.29 (td, 1H), 2.06 ( m, 4H), 1.88 (m, 3H), 1.58 (m, 2H), 1.32 (d, 6H), 1.26 (t, 3H)

Example 38: N-(2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation Example 12. The oxazol-5-yl)-piperidin-4-yl]-indole (23 mg, mp.

^{1 H-NMR (400MHz, CDCl} 3); δ 7.32 (dd, 1H), 6.96 (dd, 1H), 6.47 (br s, 1H), 4.29 (m, 1H), 3.77 (m, 2H), 3.51 ( m, 2H), 3.42 (m, 1H), 3.08 (m, 1H), 3.05 (s, 3H), 2.88 (m, 1H), 2.53 (m, 1H), 2.27 (td, 1H), 2.06 (m) , 1H), 2.00 (m, 3H), 1.89 (td, 1H), 1.82 (m, 2H), 1.58 (m, 2H), 1.28 (d, 6H)

Example 39: {2,5-Difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-urea

The compound from Preparation 16 (50 mg, 0.123 mmol) and ammonia solution (0.5 M 1,4-two) The title compound (8 mg, 14% yield) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.88 (1H, m), 7.19 (1H, d), 6.88 (1H, m), 6.55 (2H, m), 4.66 (2H, s), 4.28 (1H, m ), 3.71 (2H, m), 3.40 (3H, m), 3.05 (1H, m), 2.54 (1H, m), 2.25 (1H, m), 2.06 to 1.92 (4H, m), 1.88 (3H, m), 1.62~1.49 (2H, m)

Example 40: {2,5-Difluoro-4-[4-(1-thiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-aminecarboxylic acid methyl ester

The by-product obtained in Example 39 was purified to give the title compound (d.

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, m), 7.19 (1H, d), 6.89 (1H, m), 6.80 (1H, s), 6.55 (1H, d), 4.31 (1H, m ), 3.80 (3H, s), 3.71 (2H, m), 3.44 (3H, m), 3.06 (1H, m), 2.54 (1H, m), 2.27 (1H, m), 2.03 (4H, m) , 1.87 (3H, m), 1.65~1.51 (2H, m)

Example 41: {4-[4-(1-Benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5-difluoro-phenyl}-urea

The compound from Preparation Example 21 (50 mg, 0.112 mmol) and ammonia solution (0.5 M 1,4-two) The title compound (6 mg, yield: 11%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, m), 7.58 (2H, m), 7.28 (1H, m), 7.06 (1H, m), 6.87 (1H, m), 6.75 (1H, s ), 4.77 (2H, s), 4.34 (1H, m), 3.82 (2H, m), 3.55 (2H, m), 3.44 (1H, m), 3.05 (1H, m), 2.54 (1H, m) , 2.26 (1H, m), 2.05 (4H, m), 1.88 (3H, m), 1.60~1.50 (2H, m)

Example 42: {4-[4-(1-Benzothiazol-2-yl-piperidin-4-yloxyimino)-cyclohexyl]-2,5-difluoro-phenyl}-carbamic acid Base ester

The by-products from Example 41 were purified to give the title compound ( 4.6 mg, yield: 8%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.84 (1H, m), 7.55 (2H, m), 7.29 (1H, m), 7.06 (1H, m), 6.87 (1H, m), 6.79 (1H, s ), 4.34 (1H, m), 3.80 (5H, m), 3.56 (2H, m), 3.41 (1H, m), 3.06 (1H, m), 2.51 (1H, m), 2.26 (1H, m) , 2.05(4H,m), 1.89(3H,m),1.69~1.48(2H,m)

Example 43: 1-(4-{4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro- Phenyl)-3-(2-hydroxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-Alkyl-indole (33 mg, 0.077 mmol) and EtOAc (30 mg, EtOAc)

¹ H-NMR (400MHz, CDCl ₃ ); δ 8.22 (s, 2H), 7.89 (dd, 1H), 6.91 (br s, 1H), 6.90 (dd s, 1H), 5.36 (t, 1H), 4.34 (m, 1H), 4.20 (m, 2H), 3.84 (m, 2H), 3.57 (m, 2H), 3.50 (m, 3H), 3.09 (t, 1H), 2.55 (d, 1H), 2.50 ( m, 3H), 2.31 (td, 1H), 2.04 (m, 4H), 1.92 (td, 1H), 1.75 (m, 2H), 1.52 (m, 2H), 1.23 (t, 3H)

Example 44: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro- Phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-Alkyl-indole (30 mg, 0.070 mmol) and 3-amino-1-propanol (30 mg, 0.40 mmol)yield

¹ H-NMR (400 MHz, CDCl ₃ ); 8.22 (s, 2H), 7.88 (dd, 1H), 6.90 (dd, 1H), 6.62 (s, 1H), 5.18 (t, 1H), 4.34 (m, 1H), 4.20 (m, 2H), 3.79 (m, 2H), 3.54 (m, 5H), 3.06 (t, 1H), 2.83 (m, 1H), 2.60 (d, 1H), 2.51 (q, 2H) ), 2.31 (td, 1H), 2.05 (m, 4H), 1.92 (td, 1H), 1.75 (m, 4H), 1.52 (m, 2H), 1.23 (t, 3H)

Example 45: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Methoxy]-indole (25 mg, 0.06 mmol) and 3-hydroxy-2,2-dimethyl-propylamine were reacted in the same manner as in Example 1 to give the title compound (21 mg, yield: 64%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.84 to 7.80 (1H, m), 6.88 to 6.82 (1H, m), 6.72 (1H, s), 5.21. (1H, s), 4.32 ~4.26(1H,m),4.18~4.12(2H,m),3.53~3.48(2H,m),3.43(1H,d),3.27(2H,s),3.12(2H,d),3.04(1H , t), 2.53 (1H, d), 2.30~2.22 (1H, m), 2.11 (3H, s), 2.08~1.95 (4H, m), 1.91~1.82 (1H, m), 1.72~1.63 (2H , m), 1.55~1.47 (2H, m), 0.89 (6H, s)

Example 46: 1-(2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-isopropyl-[1,2,4] from Preparation Example 12. The oxazol-5-yl)-piperidin-4-yl]-indole (25 mg, 0.06 mmol) and 3-hydroxy-2,2-dimethyl-propylamine were reacted in the same manner as in Example 1 to give the title compound (23 mg, yield: 71%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.84 to 7.80 (1H, m), 7.88 to 7.75 (2H, m), 5.34 (1H, s), 4.31 to 4.27 (1H, m), 3.81 to 3.72 (2H, m), 3.55~3.48(2H,m), 3.43(1H,d), 3.28(2H,d),3.12(2H,d),3.04(1H,t),2.92~2.84(1H,m),2.52 (1H,d), 2.30~2.22(1H,m),2.08~1.95(4H,s),1.92~1.77(3H,m),1.55~1.45(2H,m),1.28(6H,d),0.88 (6H, s)

Example 47: (2,6-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl )-urea

4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methylpyrimidin-2-yl)-piperidine-4- obtained in Preparation Example 23. Base]-肟 (51mg, 0.121mmol) and ammonia solution (0.5M 1,4-two The title compound (45 mg, yield: 80%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 6.83 (2H, m), 5.81 (1H, s), 4.66 (2H, s), 4.30 (1H, m), 4.20 to 4.10 (2H) , m), 3.55~3.40(3H,m), 2.85(1H,m), 2.65(1H,m), 2.30~2.20(1H,m),2.15(3H,s),2.10~1.95(4H,m ), 1.90~1.80(1H,m), 1.78~1.60(2H,m), 1.50~1.40(2H,m)

Example 48: 3-Hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-guanamine

4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methylpyrimidin-2-yl)-piperidine-4 from Preparation Example 23. -Based on the title compound (45 mg, yield: 71%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 6.83 (2H, m), 5.46 (1H, s), 4.71 (1H, m), 4.35 to 4.25 (3H, m), 4.20 to 4.10 (2H,m), 4.00~3.90(2H,m),3.55~3.40(3H,m),2.71(1H,m),2.65(1H,m), 2.30~2.20(2H,m),2.15(3H , s), 2.10~1.95(4H,m), 1.90~1.80(1H,m), 1.78~1.60(2H,m), 1.50~1.40(2H,m)

Example 49: Butane-1-sulfonic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2, 5-difluoro-phenyl)-guanamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-Methoxy]-indole (40 mg, 0.093 mmol) was obtained from the title compound (25.0 mg, yield: 49%).

^{1 H-NMR (400MHz, CDCl} 3); δ 8.23 (s, 2H), 7.36 (dd, 1H), 6.70 (dd, 1H), 6.56 (br s, 1H), 4.35 (m, 1H), 4.19 ( m, 2H), 3.60 (m, 2H), 3.49 (d, 1H), 3.14 (m, 3H), 2.60 (d, 1H), 2.50 (q, 2H), 2.31 (td, 1H), 2.04 (m) , 4H), 1.95 (m, 3H), 1.76 (m, 2H), 1.52 (m, 2H), 1.47 (q, 2H), 1.23 (t, 3H), 0.96 (t, 3H)

Example 50: 4-[4-(2,5-Difluoro-4-indolylcarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester

4-[4-(4-carboxy-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid tert-butyl ester of Preparation 36 ( 60 mg, 0.13 mmol) was dissolved in dimethylformamide (5 mL). After adding triethylamine (78 mg, 0.77 mmol) and 1,1-carbonyldiimidazole (24 mg, 0.15 mmol), the mixture was stirred for 2 hr. The hydrazine hydrochloride (127 mg, 1.33 mmol) and triethylamine (150 mg, 1.48 mmol) were dissolved in dimethylformamide (4 mL) and then added, and the mixture was stirred for 2 hr. The reaction mixture was evaporated to dryness crystals crystals crystals crystals

^{1 H-NMR (400MHz, CDCl} 3); 7.62 (dd, 1H), 6.93 (dd, 1H), 6.74 (br s, 2H), 4.25 (m, 1H), 3.71 (m, 2H), 3.47 (d , 1H), 3.27 (m, 2H), 3.13 (m, 1H), 2.57 (d, 1H), 2.30 (td, 1H), 2.07 (m, 2H), 1.92 (m, 3H), 1.65 (m, 4H), 1.50 (s, 9H)

Example 51: (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl )-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethylpyrimidin-2-yl)-piperidine-4 from Preparation Example 9. -based]-肟 (0.085 mg, 0.2 mmol) and ammonia solution (0.5M 1,4-two The alkane solution was reacted in the same manner as in Example 1 to give the title compound.

NMR: ¹ H-NMR (CDCl ₃ ); δ 8.22 (s, 2H), 7.86 to 7.91 (dd, 1H), 6.89 to 6.94 (dd, 1H), 6.72 (s, NH, 1H), 4.80 (s, NH2,2H), 4.34~4.36(m,1H), 4.17~4.23(m,2H), 3.54~3.59(m,2H), 3.46~3.50(dd,1H),3.08~3.12(t,1H), 2.51~2.56(d,1H), 2.47~2.51(t,2H), 2.28~2.32(dt,1H),2.04~2.07(m,4H),1.88~1.95(dt,1H)1.18~1.77(m, 4H), 1.21~1.25(t,3H)

Example 52: (R)-3-Fluoro-pyrrolidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino) ]-cyclohexyl}-2,5-difluoro-phenyl)-guanamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-yl]-indole (30 mg, 0.070 mmol) and s-(+)-3-fluoropyridine hydrochloride (60 mg, 0.48 mmol) :89%).

^{1 H-NMR (500MHz, CDCl} 3); δ 8.16 (s, 2H), 7.96 (dd, 1H), 6.86 (dd, 1H), 6.36 (s, 1H), 5.30 (d, 1H), 4.30 (m , 1H), 4.15 (m, 2H), 3.84 (dd, 1H), 3.64 (m, 3H), 3.52 (m, 2H), 3.43 (d, 1H), 3.05 (t, 1H), 2.52 (d, 1H), 2.45 (q, 2H), 2.38 (m, 1H), 2.26 (td, 1H), 2.15 (m, 1H), 2.00 (m, 4H), 1.87 (td, 1H), 1.70 (m, 2H) ), 1.53 (m, 2H), 1.18 (t, 3H)

Example 53: (4-{4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea

4-(4-Amino-2-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 24 ]-肟(56mg, 0.136mmol) and ammonia solution (0.5M 1,4-two) The title compound (50 mg, yield: 81%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.17 (2H, s), 7.18 - 7.08 (2H, m), 6.95 - 6.93 (1H, m), 6.44 (1H, s), 4.70 (2H, s), 4.31 (1H,m), 4.20~4.10(2H,m), 3.60~3.40(3H,m),3.05(1H,m),2.55~2.40(3H,m),2.35~2.25(1H,m),2.10 ~1.90(4H,m),1.95~1.85(1H,m),1.78~1.60(2H,m), 1.50~1.40(2H,m),1.19(3H,t)

Example 54: (4-{4-[1-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl) -urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 26. -based]-肟 (20mg, 0.05mmol) and ammonia solution (0.5M 1,4-two The title compound (18 mg, yield: 82%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.21 (2H, s), 7.88 to 7.82 (1H, m), 6.90 to 6.84 (1H, m), 6.52 (1H, s), 4.64 (2H, s), 4.33 ~4.28(1H,m), 4.14~4.08(2H,m), 3.61~3.52(2H,m), 3.44(1H,d),3.05(1H,t),2.54(1H,t),2.30~2.22 (1H,m), 2.08~1.96(4H,m), 1.93~1.88(1H,m),1.76~1.68(2H,m),1.67~1.48(2H,m)

Example 55: 1-(4-{4-[1-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-benzene 3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 26. The reaction was carried out in the same manner as in Example 1 to give the title compound (19 mg, yield: 77%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.21 (2H, s), 7.88 to 7.82 (1H, m), 6.88 to 6.82 (1H, m), 6.53 (1H, s), 5.11 to 5.06 (1H, m) , 4.33~4.28(1H,m), 4.14~4.08(2H,m),3.74(2H,d),3.62~3.52(2H,m),3.48~3.40(3H,m),3.04(1H,t) , 2.76 (1H, s), 2.53 (1H, d), 2.31~2.21 (1H, m), 2.08~1.96 (4H, m), 1.93~1.88 (1H, m), 1.76~1.66 (4H, m) , 1.67~1.46(2H,m)

Example 56: 3-Hydroxy-azetidine-1-carboxylic acid {2,5-difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro- 2H-[1,2']bipyridin-4-yloxyimino)-cyclohexyl]-phenyl}-decylamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-(5'-trifluoromethyl-3,4,5,6-tetrahydrofuran from Preparation 29 -2H-[1,2']bipyridin-4-yl)-indole (40 mg, 0.085 mmol) and 3-hydroxyazetidine hydrochloride (60 mg, 0.55 mmol) were reacted in the same manner as in Example 1, Get titled Compound (16.0 mg, yield: 33%).

^{1 H-NMR (400MHz, CDCl} 3); δ 8.43 (s, 1H), 7.97 (dd, 1H), 7.65 (dd, 1H), 6.90 (dd, 1H), 6.71 (d, 1H), 6.17 (d , 1H), 4.77 (m, 1H), 4.37 (m, 3H), 3.99 (m, 4H), 3.52 (m, 3H), 3.09 (t, 1H), 2.57 (d, 1H), 2.32 (td, 1H), 2.26 (d, 1H), 2.06 (m, 4H), 1.92 (td, 1H), 1.80 (m, 2H), 1.52 (m, 2H)

Example 57: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro- Phenyl)-3-(2-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-Alkyl-indole (30 mg, 0.070 mmol) and DL-l-amino-2-propanol (35 mg, 0.47 mmol)yield ).

¹ H-NMR (500MHz, CDCl ₃ ); δ 8.16 (s, 2H), 7.83 (dd, 1H), 6.85 (dd s, 1H), 6.80 (br s, 1H), 5.15 (t, 1H), 4.30 (m,1H), 4.15 (m, 2H), 3.97 (m, 1H), 3.52 (m, 2H), 3.44 (m, 2H), 3.14 (m, 1H), 3.04 (t, 1H), 2.51 ( d,1H), 2.45 (q, 2H), 2.26 (m, 2H), 2.00 (m, 4H), 1.86 (td, 1H), 1.70 (m, 2H), 1.53 (m, 2H), 1.23 (d) , 3H), 1.18 (t, 3H)

Example 58: 1-(4-{4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4- Methoxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-Alkyl-indole (30 mg, 0.070 mmol) and 2-methoxyethylamine (35 mg, 0.48 mmol)yield

¹ H-NMR (500MHz, CDCl ₃ ); δ 8.17 (s, 2H), 7.86 (dd, 1H), 6.84 (dd s, 1H), 5.10 (t, 1H), 4.29 (m, 1H), 4.15 ( m, 2H), 3.52 (m, 4H), 3.43 (m, 3H), 3.39 (s, 3H), 3.02 (t, 1H), 2.20 (d, 1H), 2.45 (q, 2H), 2.26 (td) , 1H), 2.00 (m, 4H), 1.87 (td, 1H), 1.69 (m, 2H), 1.55 (m, 2H), 1.13 (d, 3H)

Example 59: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-ethoxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-yl]-indole (30 mg, 0.072 mmol) and 2-ethoxyethylamine (35 mg, 0.39 mmol) according to Example 1 The title compound (31.0 mg, yield: 84%) was obtained.

^{1 H-NMR (500MHz, CDCl} 3); δ 8.14 (s, 2H), 7.87 (dd, 1H), 6.85 (dd s, 1H), 5.07 (m, 1H), 4.29 (m, 1H), 4.15 ( m, 2H), 3.55 (m, 4H), 3.51 (m, 2H), 3.45 (m, 3H), 3.02 (t, 1H), 2.51 (d, 1H), 2.26 (td, 1H), 2.11 (s) , 3H), 1.99 (m, 4H), 1.87 (td, 1H), 1.69 (m, 2H), 1.55 (m, 2H), 1.22 (d, 3H)

Example 60: 1-(4-{4-[1-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-benzene 3-(2-methoxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 26. -Based on - </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

¹ H-NMR (400MHz, CDCl ₃ ); δ 8.27 (s, 2H), 7.92 (dd, 1H), 7.10 (br s, 1H), 6.89 (dd s, 1H), 5.11 (t, 1H), 4.35 (m, 1H), 4.13 (m, 2H), 3.63 (m, 4H), 3.52 (m, 3H), 3.45 (s, 3H), 3.09 (t, 1H), 2.57 (m, 1H), 2.31 ( Td, 1H), 2.05 (m, 4H), 1.92 (td, 1H), 1.76 (m, 2H), 1.52 (m, 2H)

Example 61:1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-[2-(2-hydroxy- Ethoxy)-ethyl]-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl-indole (30 mg, 0.072 mmol) and 2-(2-aminoethoxy)ethanol (40 mg, 0.38 mmol)yield %).

^{1 H-NMR (400MHz, CDCl} 3); δ 8.20 (s, 2H), 7.92 (dd, 1H), 6.91 (br s, 1H), 6.89 (dd s, 1H), 5.32 (m, 1H), 4.34 (m, 1H), 4.18 (m, 2H), 3.83 (m, 2H), 3.68 (m, 4H), 3.52 (m, 5H), 3.09 (t, 1H), 2.57 (d, 1H), 2.30 ( Td, 1H), 2.17 (m, 1H), 2.16 (s, 3H), 2.04 (m, 4H), 1.92 (td, 1H), 1.74 (m, 2H), 1.53 (m, 2H)

Example 62: {2,5-Difluoro-4-[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl Oxyimido)-cyclohexyl]-phenyl}-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-(5'-trifluoromethyl-3,4,5,6-tetrahydrofuran from Preparation 29 -2H-[1,2']bipyridin-4-yl)-indole (0.094 g, 0.2 mmol) and ammonia solution (0.5 M 1,4-two The title compound was obtained (yield: 72%).

¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.43 (s, 1H), 7.83 to 7.91 (dd, 1H), 7.63 to 7.66 (dd, 1H), 6.81 to 6.93 (dd, 1H), 6.77 (s, NH,1H), 6.70~6.73(d,1H), 4.85(s,NH2,2H), 4.36~4.38(m,1H),3.96~4.02(m,2H),3.45~3.55(m,3H), 3.08~3.12(t,1H), 2.53~2.55(d,1H), 2.28~2.34(dt,1H),2.03~2.08(m,4H),1.88~1.93(dt,1H)1.30~1.83(m, 4H)

Example 63: (2,5-Difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl )-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidine-derived from Preparation 38 4-yl]-indole (0.088g, 0.2mmol) and ammonia solution (0.5M 1,4-two The title compound was obtained (yield: 80%).

¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.19 (s, 2H), 7.87 to 7.91 (dd, 1H), 6.89 to 6.94 (dd, 1H), 6.71 (s, NH, 1H), 4.78 (s, NH2,2H), 4.32~4.38(m,1H), 4.17~4.23(m,2H), 3.56~3.59(m,2H), 3.46~3.50(m,1H),3.08~3.12(t,1H), 2.56~2.58(d,1H), 2.41~2.45(t,2H), 2.22~2.34(dt, 1H), 2.03~2.11(m,4H),1.85~1.95(dt,1H),1.68~1.80(m , 2H), 1.50~1.80 (m, 4H), 0.95~0.99 (t, 3H)

Example 64: (2,5-Difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl) -urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 40 -yl]-肟 (0.083g, 0.2mmol) and ammonia solution (0.5M 1,4-two The title compound was obtained (yield: 78%).

¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.23 (s, 2H), 7.87 to 7.92 (dd, 1H), 6.90 to 6.94 (dd, 1H), 6.56 (s, NH, 1H), 4.68 (s, NH2,2H), 4.33~4.37(m,1H), 4.10~4.22(m,2H),3.55~3.61(m,2H), 3.46~3.50(d,1H),3.06~3.14(t,1H), 2.56~2.60(d,1H), 2.28~2.34(dt,1H), 2.00~2.12(m,4H), 1.90~1.98(dt,1H), 1.50~1.80(m,4H)

Example 65: 1-(2,3-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-propyl)-urea

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexane from Preparation 57 Ketone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole and 2-hydroxy-propylamine (50 mg, 0.13 mmol) were reacted in the same manner as in Example 1, The title compound was obtained (40 mg, yield: 63%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.70 to 7.66 (1H, m), 6.91 to 6.87 (1H, m), 6.89 (1H, m), 5.30 (1H, m), 4.30 (1H,m), 4.20~4.10(2H,m), 4.00~3.90(1H,m), 3.50~3.40(4H,m), 3.20~3.00(2H,m),2.55(1H,m),2.32 ~2.22(1H,m),2.10(3H,s),2.05~1.90(4H,m),1.90~1.80(1H,m),1.72~1.60(3H,m),1.50~1.40(1H,m) , 1.22 (3H, d)

Example 66: 3-(4-{4-[1-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-benzene 1,1-dimethyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-chloro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 26. -yl]-oxime (30 mg, 0.069 mmol), dimethylamine hydrochloride (55 mg, 0.67 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) by way of example The title compound (30 mg, yield: 86%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.26 (s, 2H), 7.98 (dd, 1H), 6.90 (dd, 1H), 6.57 (s, 1H), 4.35 (m, 1H), 4.15 (m) , 2H), 3.62 (m, 2H), 3.47 (m, 1H), 3.09 (s, 6H), 3.09 (m, 1H), 2.57 (m, 1H), 2.31 (td, 1H), 2.10 (m, 4H), 1.92 (td, 1H), 1.78 (m, 2H), 1.60 (m, 2H)

Example 67: 3-(2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation Example 12. Diazol-5-yl)-piperidin-4-yl]-indole (30 mg, 0.069 mmol), dimethylamine hydrochloride (55 mg, 0.67 mmol), diisopropylethylamine (110 mg, 0.85 mmol Reaction with triphosgene (22 mg, 0.074 mmol) in the same manner as in Example 1 gave the title compound (27.5 mg, yield: 79%).

^{1 H-NMR (400MHz, CDCl} 3): δ 7.99 (dd, 1H), 6.90 (dd, 1H), 6.58 (s, 1H), 4.33 (m, 1H), 3.82 (m, 2H), 3.56 (m , 2H), 3.45 (m, 1H), 3.09 (s, 6H), 3.09 (m, 1H), 2.93 (m, 1H), 2.55 (m, 1H), 2.30 (td, 1H), 2.07 (m, 4H), 1.89 (m, 3H), 1.61 (m, 2H), 1.33 (d, 6H)

Example 68: 3-(2,6-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-1,1-dimethyl-urea

4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine of Preparation Example 23 4-based]-肟 (30mg, 0.072mmol), dimethylamine hydrochloride (55mg, 0.67mmol), diisopropylethylamine (110mg, 0.85mmol) and triphosgene (22mg, 0.074mmol) were reacted in the same manner as in Example 1 to give the title Compound (39 mg, yield: 83%).

^{1 H-NMR (400MHz, CDCl} 3): δ 8.20 (s, 2H), 6.83 (d, 2H), 5.77 (s, 1H), 4.34 (m, 1H), 4.20 (m, 2H), 3.54 (m , 2H), 3.47 (m, 1H), 3.10 (s, 6H), 2.77 (m, 1H), 2.57 (m, 1H), 2.28 (td, 1H), 2.16 (s, 3H), 2.06 (m, 4H), 1.90 (td, 1H), 1.74 (m, 2H), 1.61 (m, 2H)

Example 69: 1-(2,6-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-methoxy-ethyl)-urea

4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine of Preparation Example 23 4-yl]-indole (30 mg, 0.072 mmol), 2-methoxyethylamine (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) The title compound (31 mg, yield: 83%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.20 (s, 2H), 6.84 (d, 2H), 5.08 (t, 1H), 4.34 (m, 1H), 4.20 (m, 2H), 3.52 (m , 7H), 3.43 (s, 3H), 2.78 (m, 1H), 2.58 (m, 1H), 2.28 (td, 1H), 2.16 (s, 3H), 2.05 (m, 4H), 1.90 (td, 1H), 1.74 (m, 2H), 1.62 (m, 2H)

Example 70: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-yl]-indole (30 mg, 0.072 mmol), 2-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074) Methyl </ RTI> </ RTI> <RTI ID=0.0></RTI>

^{1 H-NMR (500MHz, CDCl} 3): δ 8.14 (s, 2H), 7.84 (dd, 1H), 6.85 (dd, 1H), 6.74 (br s, 1H), 4.84 (d, 1H), 4.29 ( m,1H), 4.13 (m, 2H), 3.98 (m, 1H), 3.75 (m, 1H), 3.58 (dd, 1H), 3.50 (m, 2H), 3.42 (d, 1H), 3.04 (t) , 1H), 2.52 (d, 1H), 2.46 (s, 1H), 2.25 (td, 1H), 2.11 (s, 3H), 1.98 (m, 4H), 1.86 (td, 1H), 1.68 (m, 2H), 1.55 (m, 2H), 1.21 (d, 3H)

Example 71:1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-methyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 a 4-tetrahydro-pyrene (30 mg, 0.072 mmol Reaction in the same manner as in Example 1 gave the title compound (29 mg, yield: 85%).

^{1 H-NMR (500MHz, CDCl} 3): δ 8.14 (s, 2H), 7.86 (dd, 1H), 6.85 (dd, 1H), 6.39 (s, 1H), 4.66 (m, 1H), 4.29 (m , 1H), 4.14 (m, 2H), 3.51 (m, 2H), 3.41 (d, 1H), 3.04 (t, 1H), 2.87 (d, 3H), 2.52 (d, 1H), 2.26 (td, 1H), 2.11 (s, 3H), 1.99 (m, 4H), 1.87 (td, 1H), 1.70 (m, 2H), 1.55 (m, 2H)

Example 72: 1-(2,5-Difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidine-derived from Preparation 38 4-yl]-indole (30 mg, 0.068 mmol), 3-amino-propan-1-ol (35 mg, 0.47 mmol), diiso The propyl ethylamine (35 mg, 0.27 mmol) and phosgene (24 mg, 0.081 mmol) were obtained to give the title compound (27.5 mg, yield: 75%).

^{1 H-NMR (500MHz, CDCl} 3): δ 8.14 (s, 2H), 7.83 (dd, 1H), 6.85 (dd, 1H), 6.56 (br s, 1H), 5.12 (t, 1H), 4.30 ( m,1H), 4.15 (m, 2H), 3.73 (m, 2H), 3.51 (m, 2H), 3.44 (m, 3H), 3.04 (t, 1H), 2.83 (s, 1H), 2.52 (d) , 1H), 2.38 (t, 2H), 2.26 (td, 1H), 2.01 (m, 4H), 1.86 (td, 1H), 1.72 (m, 4H), 1.55 (m, 4H), 0.92 (t, 3H)

Example 73: 3-Hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-guanamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-propyl-pyrimidin-2-yl)-piperidine-derived from Preparation 38 4-yl]-indole (30 mg, 0.068 mmol), azetidin-3-ol hydrochloride (55 mg, 0.50 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphos (23 mg) The title compound (28 mg, yield: 76%) was obtained.

^{1 H-NMR (500MHz, CDCl} 3): δ 8.14 (s, 2H), 7.92 (dd, 1H), 6.85 (dd, 1H), 6.12 (s, 1H), 4.72 (m, 1H), 4.31 (m , 3H), 4.15 (m, 2H), 3.96 (m, 2H), 3.51 (m, 2H), 3.41 (d, 1H), 3.04 (t, 1H), 2.52 (d, 1H), 2.38 (t, 2H), 2.26 (td, 1H), 2.20 (s, 1H), 2.01 (m, 4H), 1.86 (td, 1H), 1.70 (m, 2H), 1.54 (m, 4H), 0.92 (t, 3H) )

Example 74: 1-(2,6-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-ethyl)-urea

4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine of Preparation Example 23 4-Alkyl-indole (30 mg, 0.070 mmol) and 2-amino-1-ethanol (51 mg, 0.12 mmol)yield

NMR: ¹ H-NMR (MeOD) 8.21 (2H, s), 7.02 (2H, d), 6.36 (1H, m), 4.80 (1H, m), 4.30 (1H, m), 4.15 to 4.05 (3H, m), 3.50~3.40 (3H, m), 3.30~3.20 (1H, m), 3.15~3.05 (3H, m), 2.80 (1H, m), 2.40~2.30 (1H, m), 2.30~2.19 ( 1H, m), 2.07 (3H, s), 2.00~1.80 (5H, m), 1.65~1.45 (4H, m)

Example 75: 1-(2,6-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine of Preparation Example 23 4-yl]-indole (30 mg, 0.072 mmol), 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074) The title compound (29.5 mg, yield: 79%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.20 (s, 2H), 6.87 (d, 2H), 5.56 (s, 1H), 4.95 (t, 1H), 4.35 (m, 1H), 4.18 (m , 2H), 3.76 (m, 2H), 3.56 (m, 2H), 3.50 (m, 3H), 3.02 (s, 1H), 2.79 (m, 1H), 2.59 (d, 1H), 2.29 (td, 1H), 2.16 (s, 3H), 2.04 (m, 4H), 1.90 (td, 1H), 1.74 (m, 4H), 1.61 (m, 2H)

Example 76: 1-(2,6-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(2-hydroxy-propyl)-urea

4-(4-Amino-3,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine of Preparation Example 23 4-yl]-indole (30 mg, 0.072 mmol), 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074) The title compound (29 mg, yield: 78%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.20 (s, 2H), 6.86 (d, 2H), 6.10 (br s, 1H), 5.13 (t, 1H), 4.35 (m, 1H), 4.20 ( m, 2H), 4.02 (m, 1H), 3.52 (m, 4H), 3.18 (m, 1H), 2.79 (m, 1H), 2.59 (d, 1H), 2.50 (s, 1H), 2.28 (td) , 1H), 2.16 (s, 3H), 2.03 (m, 4H), 1.92 (td, 1H), 1.74 (m, 2H), 1.61 (m, 2H), 1.25 (d, 3H)

Example 77: 4-[4-(2-Fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester from Preparation 58 (20 mg, 0.05 Mmmol) and ammonia solution (0.5M 1,4-two The title compound (18 mg, yield: 81%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.17 (2H, m), 7.07 (1H, t), 6.96 (1H, s), 4.90 (3H, m), 4.23 (1H, m), 3.70 (2H, s ), 3.41 (1H, d), 3.28 (2H, m), 3.03 (1H, t), 2.51 (1H, d), 2.26 (1H, m), 2.04 (2H, m), 1.87 (3H, m) , 1.68 (4H, m), 1.24 (6H, d)

Example 78: 4-(4-{2-Fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneamino)-piperidine-1-carboxylate Isopropyl acrylate

4-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester from Preparation 58 (20 mg, 0.05 The title compound (15 mg, yield: 60%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.18 (2H, d), 7.04 (1H, s), 6.9 (1H, s), 5.47 (1H, s), 4.91 (1H, m), 4.22 (1H, m ), 3.70 (4H, m), 3.40 (3H, m), 3.28 (2H, m), 3.02 (1H, t), 2.61 (2H, m), 2.50 (1H, d), 2.26 (1H, m) , 2.04~1.80(5H,m),1.71~1.50(4H,m),1.24(6H,d)

Example 79: 4-(4-{4-[3-(2-Ethoxy-ethyl)-ureido]-2-fluoro-phenyl}-cyclohexylideneamino)-piperidine-1 - isopropyl carboxylic acid ester

4-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester from Preparation 58 (20 mg, 0.05 The title compound (19 mg, yield: 73%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.30 (1H, s), 7.20 (1H, d), 7.04 (1H, t), 6.94 (1H, d), 5.37 (1H, s), 4.91 (1H, m ), 4.22 (1H, m), 3.70 (2H, s), 3.54 (4H, m), 3.42 (3H, m), 3.27 (2H, m), 3.03 (1H, t), 2.50 (1H, d) , 2.26 (1H, m), 2.05~1.96 (2H, m), 1.94~1.82 (3H, m), 1.70~1.52 (4H, m), 1.24 (9H, m)

Example 80: 4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2,5-difluoro-phenyl}-cyclohexylideneamino)-peripipeline Isopropyl 1-carboxylic acid ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid isopropyl ester from Preparation Example 32 ( 20 mg, 0.05 mmol) and 2-ethoxyethylamine were reacted according to the procedure of Example 1 to give the title compound (18 mg, yield: 70%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.90 (1H, m), 7.29 (1H, bs), 6.84 (1H, m), 5.56 (1H, s), 4.91 (1H, m), 4.21. (1H, m ), 3.70 (2H, s), 3.55 (4H, m), 3.45 (3H, m), 3.27 (2H, m), 3.03 (1H, t), 2.50 (1H, d), 2.26 (1H, m) , 2.06~1.80(5H,m), 1.70~1.45(4H,m),1.26(9H,m)

Example 81: (4-{4-[1-(5-Cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-benzene Urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidine from Preparation Example 60 4-yl]-oxime (20mg, 0.05mmol) and ammonia solution (0.5M 1,4-two The title compound (15 mg, yield: 68%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.11 (2H, s), 7.85 (1H, m), 6.87 (2H, m), 4.84 (2H, s), 4.30 (1H, m), 4.12 (2H, m ), 3.51 (2H, m), 3.45 (1H, d), 3.10 (1H, m), 3.04 (1H, t), 2.53 (1H, d), 2.26 (1H, m), 1.98 (4H, m) , 1.87 (1H, m), 1.76~1.45 (4H, m), 0.89 (2H, m), 0.57 (2H, m)

Example 82: 1-(4-{4-[1-(5-Cyclopropyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro -phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-cyclopropyl-pyrimidin-2-yl)-piperidine from Preparation Example 60 4-Methoxy]-indole (20 mg, 0.05 mmol) and 3-hydroxypropylamine were reacted according to the procedure of Example 1 to give the title compound (11 mg, yield: 45%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.10 (2H, s), 7.83 (1H, m), 6.84 (2H, m), 5.52 (1H, s), 4.29 (1H, m), 4.12 (2H, m) ), 3.72 (2H, m), 3.51 (2H, m), 3.43 (3H, m), 3.03 (1H, t), 2.65 (1H, s), 2.52 (1H, d), 2.27 (1H, m) , 1.97 (4H, m), 1.86 (1H, m), 1.76~1.45 (7H, m), 0.89 (2H, m), 0.57 (2H, m)

Example 83: (2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]] Diazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea

(2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]) from Preparation 54 The oxazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-carbamic acid tert-butyl ester (85 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL). After adding trifluoroacetic acid (36 mL), the mixture was stirred at room temperature for 1 hour. The reaction was quenched under reduced pressure to remove solvent and dichloromethane (5mL). N,N-Diisopropylethylamine (83 μl, 0.479 mmol) and triphosgene (47 mg, 0.16 mmol) were added sequentially at 0 ° C, and the mixture was stirred at room temperature for 10 min. Add 0.5M ammonia two A solution of the alkane (0.96 mL, 0.479 mmol). The reaction was quenched with water, and the mixture was washed with dichloromethane and water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

NMR: ¹ H-NMR (CDCl ₃ ) 7.85 (1H, m), 6.88 (1H, m), 6.57 (1H, s), 4.68 (2H, s), 4.02 (1H, m), 3.40 (1H, m ), 3.07 (2H, m), 2.91 (1H, m), 2.50 (1H, m), 2.25 (5H, m), 2.40 (2H, m), 1.88 (1H, m), 1.73 (1H, m) , 1.50 (5H, m), 1.32 (6H, d)

Example 84: (2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]] Diazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[4-(3-isopropyl-[1,2,4], obtained from Preparation 56 The oxazol-5-yl)-cyclohexyl]-indole (38 mg, 0.088 mmol) and aq. Its polarity is higher than its isomer (the title compound of Example 83).

NMR: ¹ H-NMR (CDCl ₃ ) 7.88 (1H, m), 6.88 (1H, m), 6.55 (1H, s), 4.66 (2H, s), 4.30 (1H, m), 3.45 (1H, m ), 3.11~2.99(3H,m), 2.50(1H,m), 2.23(1H,m), 2.03~1.86(9H,m),1.68(2H,m),1.65~1.50(2H,m), 1.33(6H,d) Example 85: (2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]- Cyclohexyl}-phenyl)-dicarbodiimide diamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 was used. 4-yl]-肟 (17g, 40.92mmol) and ammonia solution (0.5M 1,4-two The title compound (390 mg, yield: 3%) was obtained from the title compound.

NMR: ¹ H-NMR (CDCl ₃ ) 9.30 (1H, s), 8.15 (2H, s), 7.95 (1H, m), 6.94 (1H, m), 4.31 (1H, m), 4.14 (2H, m) ), 3.54~3.43 (3H, m), 3.07 (1H, m), 2.53 (1H, m), 2.27 (1H, m), 2.12 (3H, s), 1.99 (4H, m), 1.88 (1H, m), 1.70~1.53 (4H, m)

Example 86: 1-(2,5-Difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzene 3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 40 -yl]-oxime (32 mg, 0.076 mmol), 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (23 mg, 0.078 mmol) Reaction in the same manner as in Example 1 gave the title compound (34 mg, yield: 86%).

^{1 H-NMR (500MHz, CDCl} 3): δ 8.18 (s, 2H), 7.83 (dd, 1H), 6.85 (dd, 1H), 6.56 (s, 1H), 5.12 (t, 1H), 4.29 (m , 1H), 4.09 (m, 2H), 3.73 (m, 2H), 3.53 (m, 2H), 3.43 (m, 3H), 3.04 (t, 1H), 2.80 (s, 1H), 2.52 (d, 1H), 2.26 (td, 1H), 2.00 (m, 4H), 1.87 (td, 1H), 1.74 (m, 4H), 1.59 (m, 2H)

Example 87: 3-Hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4- {4-[1-(5-Fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 40 -yl]-oxime (30 mg, 0.072 mmol), azetidine-3-ol hydrochloride (56 mg, 0.51 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphos (22 mg, The title compound (33.6 mg, yield: 91%) was obtained.

¹ H-NMR (500MHz, CDCl ₃ ): δ 8.18 (s, 2H), 7.92 (dd, 1H), 6.85 (dd, 1H), 6.12 (s, 1H), 4.72 (s, 1H), 4.32 (m) , 3H), 4.10 (m, 2H), 3.96 (dd, 2H), 3.54 (m, 2H), 3.42 (d, 1H), 3.04 (t, 1H), 2.52 (d, 1H), 2.26 (td, 1H), 2.19 (s, 1H), 2.00 (m, 4H), 1.87 (td, 1H), 1.70 (m, 2H), 1.55 (m, 2H)

Example 88: 1-(2,5-Difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzene 3-(2-methoxy-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexane from Preparation Example 40 Ketone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yl]-indole (30 mg, 0.072 mmol), 2-methoxy-ethylamine (35 mg, 0.47 mmol), Diisopropylethylamine (35 mg, 0.27 mmol) and phosgene (22 mg, 0.074 mmol) were obtained in the same manner as in Example 1 to give the title compound (28 mg, yield: 75%).

^{1 H-NMR (500MHz, CDCl} 3): δ 8.18 (s, 2H), 7.86 (dd, 1H), 6.84 (dd, 1H), 5.10 (t, 1H), 4.29 (m, 1H), 4.10 (m , 2H), 3.53 (m, 4H), 3.45 (m, 3H), 3.40 (s, 3H), 3.04 (t, 1H), 2.51 (d, 1H), 2.26 (td, 1H), 2.00 (m, 4H), 1.86 (td, 1H), 1.70 (m, 2H), 1.55 (m, 2H)

Example 89: 1-(2,5-Difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzene 3-isopropyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 40 -yl]-oxime (30 mg, 0.072 mmol), isopropylamine (30 mg, 0.51 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) the same as in Example 1. The title compound was obtained (24 mg, yield: 94%).

^{1 H-NMR (500MHz, CDCl} 3): δ 8.18 (s, 2H), 7.88 (dd, 1H), 6.84 (dd, 1H), 6.27 (s, 1H), 4.45 (d, 1H), 4.29 (m , 1H), 4.10 (m, 2H), 3.97 (m, 1H), 3.53 (m, 2H), 3.42 (d, 1H), 3.04 (t, 1H), 2.51 (d, 1H), 2.26 (td, 1H), 2.01 (m, 4H), 1.87 (td, 1H), 1.70 (m, 2H), 1.55 (m, 2H), 1.20 (d, 6H)

Example 90: 1-(2,5-Difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzene 3-(2-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 40 -yl]-oxime (30 mg, 0.072 mmol), 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) Reaction in the same manner as in Example 1 gave the title compound (32 mg, yield: 86%).

^{1 H-NMR (500MHz, DMSO} ): δ 8.51 (s, 1H), 8.40 (s, 2H), 7.91 (dd, 1H), 7.14 (dd, 1H), 6.74 (t, 1H), 4.74 (s, 1H), 4.20 (m, 1H), 4.04 (m, 2H), 3.41 (m, 2H), 3.22 (d, 2H), 3.09 (m, 1H), 2.93 (m, 2H), 2.34 (m, 1H) ), 2.24 (td, 1H), 1.88 (m, 5H), 1.50 (m, 4H), 1.00 (d, 3H)

Example 91:1-(2,5-Difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzene 3-thiophen-2-ylmethyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-fluoro-pyrimidin-2-yl)-piperidine-4 from Preparation Example 40 -基]-肟 (30mg, 0.072 Methyl), thiophen-2-ylmethyl-amine (35 mg, 0.31 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) were obtained in the same manner as in Example 1. The title compound (35 mg, yield: 88%).

^{1 H-NMR (500MHz, CDCl} 3): δ 8.18 (s, 2H), 7.88 (dd, 1H), 7.232 (d, 1H), 7.00 (d, 1H), 6.95 (dd, 1H), 6.84 (dd , 1H), 6.45 (s, 1H), 5.06 (t, 1H), 4.62 (d, 2H), 4.29 (m, 1H), 4.10 (m, 2H), 3.53 (m, 2H), 3.42 (d, 1H), 3.04 (t, 1H), 2.51 (d, 1H), 2.25 (td, 1H), 2.01 (m, 4H), 1.88 (td, 1H), 1.70 (m, 2H), 1.58 (m, 2H) )

Example 92: (2-Fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 49 ]-肟 (100mg, 0.25mmol) and ammonia solution (0.5M 1,4-two The title compound (100 mg, yield: 90%) was obtained.

NMR: ¹ H-NMR (DMSO) 8.21 (s, 2H), 7.97 (t, 1H), 7.09 (d, 1H), 6.97 (d, 1H), 6.10 (s, 2H), 4.23 (m, 1H) , 4.11 (m, 2H), 3.43 (m, 2H), 3.25 (d, 1H), 2.74 (t, 1H), 2.39 (d, 1H), 2.27 (m, 1H), 2.07 (s, 3H), 1.91 (m, 5H), 1.60 (m, 4H)

Example 93: (2,3-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)- Piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation 57 4-based]-肟 and ammonia solution (0.5M 1,4-two The title compound (48 mg, yield 85%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.69 to 7.66 (1H, m), 6.93 to 6.89 (1H, m), 6.46 (1H, s), 4.68 (2H, s), 4.30 (1H,m), 4.20~4.10(2H,m), 3.60~3.40(3H,m),3.10(1H,m), 2.60(1H,m), 2.32~2.20(1H,m),2.15(3H , s), 2.10~1.95 (4H, m), 1.91~1.81 (1H, m), 1.75~1.62 (3H, m), 1.50~1.40 (1H, m)

Example 94: 3-Hydroxy-azetidine-1-carboxylic acid (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-guanamine

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation 57 4-Alkyl-indole and 3-hydroxyazetidine hydrochloride (20 mg, 0.22 mmol)yield

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.82 to 7.78 (1H, m), 6.94 to 6.89 (1H, m), 6.09 (1H, s), 4.73 (1H, m), 4.35 ~4.22(3H,m), 4.22~4.10(2H,m), 4.00~3.90(2H,m),3.58~3.40(3H,m),3.04(1H,m),2.52(1H,d),2.32 ~2.20(1H,m), 2.20~2.15(1H,m),2.11(3H,s), 2.10~1.95(4H,m),1.90~1.80(1H,m),1.78~1.60(2H,m) , 1.50~1.40 (2H, m)

Example 95: 1-(2,3-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation 57 4-Alkyl-indole and 3-amino-1-propanol (51 mg, 0.12 mmol)yield

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.67 to 7.60 (1H, m), 6.90 to 6.85 (1H, m), 6.39 (1H, s), 5.02 (1H, m), 4.30 (1H,m), 4.15~4.05(2H,m), 3.80~3.70(2H,m),3.55~3.40(5H,m),3.06(1H,m),2.52(1H,m),2.58~2.49 (1H,m), 2.30~2.20(1H,m),2.11(3H,s), 2.10~1.95(4H,m),1.90~1.80(1H,m),1.80~1.60(6H,m)

Example 96: 1-(2-Fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl) -3-(3-hydroxy-propyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 49 ]-肟 (30 mg, 0.072 mmol), 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074 mmol) The title compound (25.4 mg, yield 67%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.20 (s, 2H), 7.85 (t, 1H), 6.99 (m, 2H), 6.41 (s, 1H), 5.03 (t, 1H), 4.34 (m , 1H), 4.20 (m, 2H), 3.76 (q, 2H), 3.52 (m, 5H), 3.02 (t, 1H), 2.77 (t, 1H), 2.57 (d, 1H), 2.28 (td, 1H), 2.16 (s, 3H), 2.03 (m, 4H), 1.91 (td, 1H), 1.77 (m, 4H), 1.60 (m, 2H)

Example 97: 3-Hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxy) Imino]-cyclohexyl}-phenyl)-decylamine

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 49 ]-肟 (30 mg, 0.072 mmol), azetidine-3-ol hydrochloride (50 mg, 0.46 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphosgene (22 mg, 0.074 mmol) Reaction in the same manner as in Example 1 gave the title compound (25.3 mg, yield 65%).

^{1 H-NMR (400MHz, CDCl} 3): δ 8.19 (s, 2H), 8.05 (t, 1H), 7.00 (d, 1H), 6.94 (d, 1H), 6.14 (s, 1H), 4.75 (m , 1H), 4.35 (m, 3H), 4.19 (m, 2H), 4.00 (dd, 2H), 3.55 (m, 2H), 3.46 (m, 1H), 2.76 (m, 1H), 2.56 (m, (1), 2.

Example 98: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro- Phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine-derived from Preparation 48 4-yl]-indole (30 mg, 0.070 mmol), 3-amino-propan-1-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (21 mg, 0.071) The title compound (31.9 mg, yield 86%) was obtained.

¹ H-NMR (400MHz, CDCl ₃ ): δ 8.22 (s, 2H), 7.71 (td, 1H), 6.94 (td, 1H), 6.56 (s, 1H), 5.16 (t, 1H), 4.35 (m) , 1H), 4.20 (m, 2H), 3.78 (q, 2H), 3.55 (m, 5H), 3.10 (m, 1H), 2.87 (s, 1H), 2.58 (d, 1H), 2.50 (q, 2H), 2.31 (td, 1H), 2.07 (m, 4H), 1.92 (td, 1H), 1.76 (m, 6H), 1.23 (t, 3H)

Example 99: 3-Hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino] -cyclohexyl}-2,3-difluoro-phenyl)-guanamine

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine-derived from Preparation 48 4-yl]-indole (30 mg, 0.070 mmol), azetidin-3-ol hydrochloride (50 mg, 0.47 mmol), diisopropylethylamine (110 mg, 0.85 mmol) and triphos (22 mg) Reaction of the title compound (30.3 mg, yield 82%).

^{1 H-NMR (400MHz, CDCl} 3): δ 8.21 (s, 2H), 7.85 (t, 1H), 6.93 (t, 1H), 6.13 (s, 1H), 4.77 (m, 1H), 4.36 (m , 3H), 4.20 (m, 2H), 4.02 (m, 2H), 3.55 (m, 3H), 3.09 (m, 1H), 2.58 (d, 1H), 2.50 (q, 2H), 2.30 (m, 2H), 2.05 (m, 4H), 1.92 (td, 1H), 1.74 (m, 4H), 1.23 (t, 3H)

Example 100: (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl )-urea

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine-derived from Preparation 48 4-yl]-肟 (30mg, 0.070mmol), 0.5N ammonia Alkane solution (1.5 mL, 1.5 mmol), diisopropylethylamine (35 mg, 0.27 mmol) %).

^{1 H-NMR (400MHz, CDCl} 3): δ 8.22 (s, 2H), 7.23 (t, 1H), 6.96 (t, 1H), 6.50 (s, 1H), 4.70 (s, 2H), 4.35 (m , 1H), 4.20 (m, 2H), 3.55 (m, 3H), 3.11 (m, 1H), 2.57 (m, 1H), 2.50 (q, 2H), 2.31 (td, 1H), 2.04 (m, 4H), 1.90 (td, 1H), 1.74 (m, 4H), 1.23 (t, 3H)

Example 101:1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro- Phenyl)-3-(2-hydroxy-propyl)-urea

4-(4-Amino-2,3-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine-derived from Preparation 48 4-yl]-indole (30 mg, 0.070 mmol), 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (22 mg, 0.074) The title compound (31.9 mg, yield 86%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.22 (s, 2H), 7.72 (td, 1H), 6.94 (td, 1H), 6.81 (br s, 1H), 5.26 (t, 1H), 4.35 ( m, 1H), 4.20 (m, 2H), 4.03 (m, 1H), 3.53 (m, 4H), 3.20 (m, 1H), 3.10 (m, 1H), 2.58 (d, 1H), 2.50 (q) , 2H), 2.37 (d, 1H), 2.31 (td, 1H), 2.06 (m, 4H), 1.92 (td, 1H), 1.73 (m, 4H), 1.28 (d, 3H), 1.23 (t, 3H)

Example 102: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro- Phenyl)-3-propyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-yl]-indole (30 mg, 0.070 mmol), propylamine hydrochloride (50 mg, 0.52 mmol), diisopropylethylamine (105 mg, 0.81 mmol) and triphosgene (21 mg, 0.071 mmol) The reaction was carried out in the same manner to give the title compound (yield: 73%).

^{1 H-NMR (400MHz, CDCl} 3): δ 8.22 (s, 2H), 7.92 (dd, 1H), 6.90 (dd, 1H), 6.40 (s, 1H), 4.71 (t, 1H), 4.34 (m , 1H), 4.20 (m, 2H), 3.57 (m, 2H), 3.47 (d, 1H), 3.28 (q, 2H), 3.09 (t, 1H), 2.57 (d, 1H), 2.50 (q, 2H), 2.31 (td, 1H), 2.04 (m, 4H), 1.90 (td, 1H), 1.75 (m, 2H), 1.61 (m, 4H), 1.23 (t, 3H), 1.00 (t, 3H) )

Example 103: 4-[4-(3-Fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester from Preparation 59 (20 mg, 0.05 Mmmol) and ammonia solution (0.5M 1,4-two The title compound (20 mg, yield 90%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, t), 6.95 (1H, d), 6.92 (1H, d), 6.68 (1H, s), 4.92 (1H, m), 4.76 (2H, s ), 4.22 (1H, m), 3.70 (2H, m), 3.41 (1H, d), 3.27 (2H, m), 2.72 (1H, t), 2.51 (1H, d), 2.24 (1H, m) , 2.10~1.96(2H,m), 1.92~1.80(3H,m), 1.70~1.48(4H,m),1.24(6H,d)

Example 104: (2,5-Difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-trifluoromethyl-pyrimidin-2-yl)-perpartate from Preparation 61 Pyridin-4-yl]-indole (20 mg, 0.04 mmol) and ammonia solution (0.5 M 1,4-two The title compound (16 mg, yield 73%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.46 (2H, s), 7.84 (1H, m), 6.98 (1H, s), 6.86 (1H, m), 4.90 (2H, s), 4.33 (1H, m ), 4.15 (2H, m), 3.72 (2H, m), 3.44 (1H, d), 3.04 (1H, t), 2.53 (1H, d), 2.26 (1H, m), 2.08 to 1.95 (4H, m), 1.90 (1H, m), 1.75 (2H, m), 1.65~1.48 (2H, m)

Example 105: (4-{4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 47 ]-肟(41mg, 0.1mmol) and ammonia solution (0.5M 1,4-two) The title compound (43 mg, yield 95%) was obtained.

NMR: ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.22 (s, 2H), 7.85 to 7.89 (t, 1H), 6.96 to 7.03 (m, 2H), 6.51 (s, NH, 1H), 4.70 ( s, NH2, 2H), 4.33~4.37 (m, 1H), 4.12~4.21 (m, 2H), 3.54~3.59 (m, 2H), 3.46~3.49 (d, 1H), 2.72~2.81 (t, 1H) ), 2.56~2.60(d,1H), 2.47~2.53(q,2H), 2.22~2.32(dt,1H), 2.00~2.12(m,4H),1.86~1.92(dt,1H),1.52~1.76 (m, 4H), 1.21~1.25(t,3H)

Example 106: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl) -3-(3-hydroxy-propyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone from Preparation 47 O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-indole (33 mg, 0.080 mmol), 3-amino-propan-1-ol (35 mg, 0.47 mmol) Diisopropylethylamine (35 mg, 0.27 mmol) and phosgene (23 mg, 0.078 mmol).

¹ H-NMR (500MHz, CDCl ₃ ): δ 8.16 (s, 2H), 7.79 (t, 1H), 6.95 (d, 1H), 6.91 (d, 1H), 6.40 (s, 1H), 5.02 (t , 1H), 4.30 (m, 1H), 4.15 (m, 2H), 3.71 (m, 2H), 3.51 (m, 2H), 3.43 (m, 3H), 3.02 (s, 1H), 2.72 (t, 1H), 2.51 (d, 1H), 2.45 (q, 2H), 2.23 (td, 1H), 2.01 (m, 4H), 1.86 (td, 1H), 1.71 (m, 4H), 1.60 (m, 2H) ), 1.18 (t, 3H)

Example 107: 1-(4-{4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl) -3-(2-hydroxy-propyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 47 ]-肟 (33 mg, 0.080 mmol), 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (23 mg, 0.078 mmol) The title compound (38 mg, yield: 92%) was obtained.

^{1 H-NMR (500MHz, CDCl} 3): δ 8.16 (s, 2H), 7.82 (t, 1H), 7.00 (d, 1H), 6.90 (d, 1H), 6.62 (s, 1H), 5.16 (t , 1H), 4.30 (m, 1H), 4.15 (m, 2H), 3.97 (m, 1H), 3.51 (m, 2H), 3.43 (m, 2H), 3.14 (m, 1H), 2.71 (t, 1H), 2.46 (m, 4H), 2.23 (td, 1H), 2.01 (m, 4H), 1.85 (td, 1H), 1.70 (m, 2H), 1.58 (m, 2H), 1.20 (m, 6H) )

Example 108: 3-Hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino] -cyclohexyl}-2-fluoro-phenyl)-decylamine

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 47 ]-肟 (33 mg, 0.080 mmol), azetidine-3-ol hydrochloride (50 mg, 0.47 mmol), diisopropylethylamine (113 mg, 0.87 mmol) and triphosgene (22 mg, 0.074 mmol) Reaction in the same manner as in Example 1 gave the title compound (31 mg, yield 76%).

^{1 H-NMR (500MHz, CDCl} 3): δ 8.16 (s, 2H), 8.00 (t, 1H), 6.93 (d, 1H), 6.88 (d, 1H), 6.09 (s, 1H), 4.71 (m , 1H), 4.29 (m, 3H), 4.15 (m, 2H), 3.95 (dd, 2H), 3.52 (m, 2H), 3.41 (m, 1H), 2.71 (t, 1H), 2.52 (m, 1H), 2.45 (q, 2H), 2.23 (m, 2H), 2.20 (m, 4H), 1.86 (td, 1H), 1.69 (m, 2H), 1.57 (m, 2H), 1.19 (m, 3H) )

Example 109: 4-Methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylate Acid ethyl ester

2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.02 g, 14.51 mmol) was reacted in the same manner as in Preparations 1, 2 and 3 to give 4-methyl-2-(4) - pendant oxy-cyclohexyl)-thiazole-5-carboxylic acid ethyl ester. This compound was reacted with O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-hydroxylamine to give the title compound ( 142 mg).

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 4.37 to 4.20 (3H, m), 4.19 to 4.10 (2H, m), 3.52 to 3.45 (2H, m), 3.40 to 3.30 (1H, m), 3.19 (1H, m), 2.70 (3H, s), 2.67~2.57 (1H, m), 2.35~2.21 (3H, m), 2.11 (3H, s), 2.05~1.95 (3H, m) , 1.85~1.60(4H,m), 1.36(3H,t)

Example 110: 4-Methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylate Acid (2-fluoro-ethyl)-decylamine

From 4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid The base ester (150 mg, 0.327 mmol) was reacted according to the procedure of Preparation 36 to give 4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxy Imino]-cyclohexyl}-thiazole-5-carboxylic acid (26 mg, 0.065 mmol). This compound is soluble in N,N-dimethyl A Indoleamine (2 mL), EDC (15 mg, 0.0786 mmol), HOBT (11 mg, 0.0786 mmol), 2-fluoroethylamine (7.0 mg, 0.066 mmol) and triethylamine (0.03 mL, 0.24 mmol) . The mixture was stirred at room temperature for 1 hour, and the reaction solution was evaporated under reduced pressure and ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The organic layer was evaporated under reduced pressure and purified to purified

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 6.06 (1H, m), 4.64 (1H, t), 4.52 (1H, t), 4.30 (1H, m), 4.20 to 4.10 (2H) , m), 3.80~3.67(2H,m), 3.58~3.45(2H,m), 3.40~3.30(1H,m),3.20(1H,m),2.67(3H,s),2.60~2.50(1H , m), 2.35~2.20(3H,m), 2.11(3H,s), 2.05~1.95(3H,m),1.89~1.60(4H,m)

Example 111: 4-(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4- Base]-肟

Taking 4-methyl-2-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid B The ester (150 mg, 0.327 mmol) was obtainedjjjjjjjjjj

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 4.94 (2H, s), 4.30 (1H, m), 4.19 to 4.10 (2H, m), 3.55 to 3.45 (2H, m), 3.40 ~3.30(1H,m), 3.19(1H,m), 2.67~2.57(1H,m), 2.28(3H, s), 2.32~2.15(3H,m),2.11(3H,s),2.05~1.95 (3H,m), 1.85~1.60 (5H,m)

Example 112: 3-Hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidine 4-yloxyimino]-cyclohexyl}-phenyl)-guanamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-trifluoromethyl-pyrimidin-2-yl)-perpartate from Preparation 61 Pyridin-4-yl]-indole (20 mg, 0.04 mmol) and 3-hydroxy-azetidine hydrochloride were reacted in the same manner as in Example 1 to give the title compound (15 mg, yield 62%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.46 (2H, s), 7.94 (1H, m), 6.87 (1H, m), 6.12 (1H, s), 4.72 (1H, m), 4.33 (3H, m ), 4.15 (2H, m), 3.95 (2H, m), 3.72 (2H, m), 3.44 (1H, m), 3.04 (1H, t), 2.53 (1H, d), 2.30~2.15 (2H, m), 2.08~1.95(4H,m), 1.88(1H,m), 1.76(2H,m),1.65~1.48(2H,m)

Example 113: 4-(4-{3-Fluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexylideneamino)-peripipeline Isopropyl 1-carboxylic acid ester

4-[4-(4-Amino-3-fluoro-phenyl)-subring from Preparation 59 The hexylaminooxy]-piperidine-1-carboxylic acid isopropyl ester (20 mg, 0.05 mmol) and 3-hydroxy-azetidine hydrochloride were reacted in the same manner as in Example 1 to give the title compound (21 mg) , yield 84%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.03 (1H, t), 6.95 (1H, d), 6.90 (1H, d), 6.09 (1H, s), 4.90 (1H, m), 4.73 (1H, m) ), 4.32 (2H, t), 4.21 (1H, m), 3.97 (2H, m), 3.72 (2H, m), 3.41 (1H, m), 3.28 (2H, m), 2.72 (1H, m) , 2.51 (1H, m), 2.24 (1H, m), 2.18 (1H, d), 2.10~1.96 (2H, m), 1.92~1.80 (3H, m), 1.70~1.40 (4H, m), 1.24 (6H,d)

Example 114: 1-(2,5-Difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl }-phenyl)-3-(2-hydroxy-propyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(4-trifluoromethyl-pyrimidin-2-yl)-perpartate from Preparation 46 Pyridin-4-yl]-indole (32 mg, 0.068 mmol), 1-amino-propan-2-ol (35 mg, 0.47 mmol), diisopropylethylamine (35 mg, 0.27 mmol) and triphosgene (21 mg) The title compound (25.7 mg, yield 66%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.52 (s, 1H), 7.89 (dd, 1H), 6.90 (dd, 1H), 6.85 (br s, 1H), 6.76 (d, 1H), 5.23 ( t, 1H), 4.38 (m, 1H), 4.21 (m, 2H), 4.04 (m, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 3.19 (m, 1H), 3.09 (t) , 1H), 2.58 (d, 1H), 2.31 (m, 1H), 2.05 (m, 4H), 1.93 (td, 1H), 1.79 (m, 2H), 1.61 (m, 2H), 1.28 (d, 3H)

Example 115: 3-Hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidine 4-yloxyimino]-cyclohexyl}-phenyl)-guanamine

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(4-trifluoromethyl-pyrimidin-2-yl)-perpartate from Preparation 46 Pyridin-4-yl]-indole (32 mg, 0.068 mmol), azetidin-3-ol hydrochloride (45 mg, 0.41 mmol), diisopropylethylamine (113 mg, 0.87 mmol) and triphos (21 mg, 0.071 mmol.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.52 (s, 1H), 7.98 (dd, 1H), 6.90 (dd, 1H), 6.91 (d, 1H), 6.17 (s, 1H), 4.77 (m , 1H), 4.36 (m, 3H), 4.21 (m, 2H), 4.01 (dd, 2H), 3.71 (m, 2H), 3.48 (d, 1H), 3.10 (t, 1H), 2.57 (d, 1H), 2.31 (td, 1H), 2.22 (m, 1H), 2.05 (m, 4H), 1.93 (td, 1H), 1.79 (m, 2H), 1.61 (m, 2H)

Example 116: [(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-1-(4- {4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzyl)-2-oxo-ethyl]- Tert-butyl carbamate

{(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-2-yloxy-1-[4-(4-sideoxy-ring) from Preparation 45 Benzyl)-benzyl]-ethyl}-carbamic acid tert-butyl ester (34 mg, 0.079 mmol) and O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl The -hydroxyamine was reacted in the same manner as in Preparation 5 to give the title compound (44 mg, yield: 90%).

¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.19 (s, 2H), 7.07 (m, 4H), 5.38 (dd, 1H), 5.13 (dd, 1H), 4.57 (m, 1H), 4.34 (m) , 1H), 4.19 (m, 2H), 3.84 (m, 1H), 3.70 to 3.30 (m, 5H), 3.10 to 2.70 (m, 4H), 2.56 (m, 1H), 2.29 (m, 1H), 2.16(s,3H), 2.12~2.00(m,6H), 1.87(m,1H), 1.80~1.50(m,4H),1.45(s,9H)

Example 117: 4-{4-[(S)-2-Amino-3-((S)-3-fluoro-pyrrolidin-1-yl)-3-oxo-propyl]-phenyl} -cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

[(S)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-1-(4-{4-[1-(5-methyl-pyrimidine-2) from Example 116 -yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (41.2 mg, 0.066 mmol) Trifluoroacetic acid (3 mL) was added to dichloromethane (3 mL). After the reaction was completed, the solvent was removed under reduced pressure. The residue was dissolved in a small amount of dichloromethane and diethyl ether was added. The solid which formed was filtered and dried to give the title compound (25 mg, yield 52%).

¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.20 (s, 2H), 7.19 (s, 4H), 5.08 (dd, 1H), 4.40 to 4.15 (m, 4H), 3.85 (m, 1H), 3.57 (m, 2H), 3.50~3.25 (m, 5H), 3.10 (m, 1H), 2.80~2.55 (m, 4H), 2.26 (m, 2H), 2.16 (s, 3H), 2.04 (m, 5H) ), 1.90 (m, 2H), 1.80~1.50 (m, 3H)

Example 118: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro- Phenyl)-3-methyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 a 4-tetrahydro-pyrene (33 mg, 0.077 mmol Reaction in the same manner as in Example 1 gave the title compound (25 mg, yield 67%).

^{1 H-NMR (400MHz, CDCl} 3): δ 8.22 (s, 2H), 7.91 (dd, 1H), 6.90 (dd, 1H), 6.41 (s, 1H), 4.66 (m, 1H), 4.35 (m , 1H), 4.21 (m, 2H), 3.57 (m, 2H), 3.49 (m, 1H), 3.09 (m, 1H), 2.92 (d, 3H), 2.51 (m, 3H), 2.30 (td, 1H), 2.05 (m, 4H), 1.92 (td, 1H), 1.75 (m, 2H), 1.60 (m, 2H), 1.23 (t, 3H)

Example 119: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-propyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-yl]-indole (35 mg, 0.084 mmol), propylamine (40 mg, 0.68 mmol), diisopropylethylamine (40 mg, 0.31 mmol) and triphosgene (25 mg, 0.084 mmol) the same as in Example 1. The title compound (33 mg, yield 78%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.20 (s, 2H), 7.92 (dd, 1H), 6.90 (dd, 1H), 6.42 (s, 1H), 4.73 (t, 1H), 4.34 (m , 1H), 4.20 (m, 2H), 3.55 (m, 2H), 3.48 (m, 1H), 3.28 (q, 2H), 3.09 (t, 1H), 2.57 (d, 1H), 2.31 (td, 1H), 2.16 (s, 3H), 2.04 (m, 4H), 1.92 (td, 1H), 1.75 (m, 2H), 1.61 (m, 4H), 1.00 (t, 3H)

Example 120: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro- Phenyl)-3-isopropyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 9 4-yl]-indole (35 mg, 0.081 mmol), isopropylamine (40 mg, 0.68 mmol), diisopropylethylamine (40 mg, 0.31 mmol) and triphosgene (24 mg, 0.081 mmol) according to Example 1. The title compound (31 mg, yield 74%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.22 (s, 2H), 7.92 (dd, 1H), 6.89 (dd, 1H), 6.35 (s, 1H), 4.51 (d, 1H), 4.35 (m , 1H), 4.19 (m, 2H), 4.03 (m, 1H), 3.57 (m, 2H), 3.48 (d, 1H), 3.09 (t, 1H), 2.57 (d, 1H), 2.50 (q, 2H), 2.31 (td, 1H), 2.04 (m, 4H), 1.92 (td, 1H), 1.75 (m, 2H), 1.60 (m, 2H), 1.24 (m, 9H)

Example 121:1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-isopropyl-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-yl]-indole (35 mg, 0.084 mmol), isopropylamine (40 mg, 0.68 mmol), diisopropylethylamine (40 mg, 0.31 mmol) and triphosgene (25 mg, 0.084 mmol) according to Example 1. The title compound (29 mg, yield 69%) was obtained.

^{1 H-NMR (400MHz, CDCl} 3): δ 8.20 (s, 2H), 7.92 (dd, 1H), 6.89 (dd, 1H), 6.35 (s, 1H), 4.52 (d, 1H), 4.34 (m , 1H), 4.19 (m, 2H), 4.03 (m, 1H), 3.56 (m, 2H), 3.48 (m, 1H), 3.09 (t, 1H), 2.57 (d, 1H), 2.30 (td, 1H), 2.16 (s, 3H), 2.05 (m, 4H), 1.92 (td, 1H), 1.75 (m, 2H), 1.60 (m, 2H), 1.25 (d, 6H)

Example 122: 4-[4-(2-Fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester

1-Chloro-2-fluoro-4-nitro-benzene (0.20 g, 1.13 mmol) was reacted in the same manner as in Preparations 1, 2, 3 and 5 to give 4-[4-(4-amino)- Tert-butyl 2-fluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylate. The compound was reacted with phenyl chloroformate to give the title compound (0.18 g, mp.

NMR: ¹ H-NMR (CDCl ₃ ) 7.42~7.30 (5H, m), 7.25 (1H, m), 7.20~7.08 (6H, m), 7.06 (1H, d), 6.94 (1H, s), 4.30 (1H, m), 3.88 (1H, s), 3.78 (1H, s), 3.54 (1H, s), 3.46 (2H, d), 3.08 (1H, t), 2.54 (1H, d), 2.30 ( 1H,m), 2.10~1.98(4H,m),1.91(1H,m),1.78(2H,m),1.74~1.55(2H,m)

Example 123: 4-[4-(3-Fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester

4-Chloro-2-fluoro-1-nitro-benzene (0.2 g, 1.13 mmol) was reacted in the same manner as in Preparations 1, 2, 3 and 5 to give 4-[4-(4-amino)- 3-Fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester. This compound was reacted with phenyl chloroformate in the same manner as in Preparation 32 to give the title compound (0.16 g, mp.

NMR: ¹ H-NMR (CDCl ₃ ) 8.02 (1H, s), 1.42 to 1.32 (4H, m), 7.30 to 7.15 (4H, m), 7.11 (3H, d), 7.02 (2H, m), 4.30 (1H, m), 3.87 (1H, s), 3.78 (1H, s), 3.53 (1H, s), 3.45 (2H, d), 2.76 (1H, t), 2.54 (1H, d), 2.27 ( 1H,m), 2.12~1.96(4H,m), 1.90(1H,m),1.78(2H,s),1.60~1.40(2H,m)

Example 124: 4-[4-(2,5-Difluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester

The title compound (40 mg, yield 26%) was obtained from the by-products.

NMR: ¹ H-NMR (CDCl ₃ ) 7.42 to 7.32 (6H, m), 7.28 (1H, m), 7.20 to 7.12 (4H, m), 7.11 to 7.05 (2H, m), 4.30 (1H, m) , 3.87 (1H, s), 3.78 (1H, s), 3.57~3.38 (3H, m), 3.14 (1H, t), 2.57 (1H, d), 2.31 (1H, m), 2.14~2.04 (2H , m), 2.00 (2H, s), 1.92 (1H, m), 1.78 (2H, s), 1.71~1.56 (2H, m)

Example 125: 4-{4-[2,5-Difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid phenyl ester of Preparation 62 (15 mg) Reaction with propylamine in the same manner as in Example 1 gave the title compound (11 mg, yield 62%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.90 (1H, m), 7.34 (2H, t), 7.20 (1H, t), 7.10 (2H, d), 6.85 (1H, m), 6.68 (1H, m ), 4.91 (1H, m), 4.29 (1H, m), 3.87 (1H, s), 3.78 (1H, s), 3.53 (1H, s), 3.44 (2H, d), 3.15 (2H, s) , 3.05 (1H, t), 2.53 (1H, d), 2.28 (1H, m), 2.10~1.95 (4H, m), 1.90 (1H, m), 1.79 (2H, s), 1.70~1.45 (4H , m), 0.92 (3H, s)

Example 126: 4-{4-[4-(3,3-Dimethyl-ureido)-2,5-difluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylate Acid phenyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid phenyl ester of Preparation 62 (15 mg) Reaction with dimethylamine hydrochloride in the same manner as in Example 1 to give the title compound (10 mg, yield 57%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.94 (1H, m), 7.35 (2H, t), 7.18 (1H, t), 7.11 (2H, d), 6.87 (1H, m), 6.52 (1H, s ), 4.29 (1H, m), 3.86 (1H, s), 3.77 (1H, s), 3.53 (1H, s), 3.44 (2H, d), 3.10~3.00 (7H, m), 2.53 (1H, d), 2.28 (1H, m), 2.10~1.95 (4H, m), 1.90 (1H, m), 1.78 (2H, s), 1.70~1.48 (2H, m)

Example 127: 4-(4-{2,5-Difluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexyleneaminooxy )-piperidine-1-carboxylic acid phenyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid phenyl ester of Preparation 62 (15 mg) Reaction with 3-hydroxyazetidine hydrochloride in the same manner as in Example 1 to give the title compound (12 mg, yield: 65%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.93 (1H, m), 7.35 (2H, t), 7.18 (1H, t), 7.11 (2H, d), 6.86 (1H, m), 6.13 (1H, s ), 4.69 (1H, m), 4.29 (3H, m), 3.96 (2H, m), 3.88 (1H, s), 3.78 (1H, s), 3.54 (1H, s), 3.44 (2H, d) , 3.05 (1H, t), 2.74 (1H, d), 2.53 (1H, d), 2.28 (1H, m), 2.10 to 1.95 (4H, m), 1.90 (1H, m), 1.78 (2H, s ), 1.68~1.48(2H,m)

Example 128: 4-{4-[2,5-Difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid benzene Base ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid phenyl ester of Preparation 62 (15 mg) Reaction with isopropylamine in the same manner as in Example 1 to give the title compound (13 mg, yield 73%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.92 (1H, m), 7.34 (2H, t), 7.18 (1H, t), 7.10 (2H, d), 6.83 (1H, m), 6.65 (1H, s ), 4.84 (1H, s), 4.29 (1H, m), 3.94 (2H, m), 3.77 (1H, s), 3.54 (1H, s), 3.44 (2H, d), 3.04 (1H, t) , 2.52 (1H, d), 2.26 (1H, m), 2.10~1.95 (4H, m), 1.90 (1H, m), 1.79 (2H, s), 1.68~1.48 (2H, m), 1.14 (6H) , d)

Example 129: 3-Hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[(Z)-1-(5-methyl-pyrimidin-2-yl)- Piperidin-4-yloxyimino]-cyclohex-1-enyl}-phenyl)-decylamine

4-Bromo-2,5-difluoronitrobenzene (1.5 g, 6.26 mmol) was reacted in the same manner as in Preparations 1, 50, 3 and 7 to give a compound. The compound was reacted with 3-hydroxyazetidine hydrochloride (11 mg, 0.10 mmol

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.97 to 7.92 (1H, m), 6.93 to 6.90 (1H, m), 6.17 (1H, s), 6.00 (0.3H, m), 5.90 (0.7H, m), 4.71 (1H, m), 4.35~4.22 (3H, m), 4.20~4.10 (2H, m), 4.00~3.90 (2H, m), 3.59~3.41 (2H, m) , 3.20 (1.3H, m), 3.04 (0.7H, m), 2.75 (1H, m), 2.65~2.50 (4H, m), 2.11 (3H, s), 2.10~1.95 (2H, m), 1.80 ~1.70(2H,m)

Example 130: 4-{4-[3-Fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester of Preparation 71 (70 mg, 0.16 mmol) Reaction with propylamine in the same manner as in Example 1 to give the title compound (56 mg, yield 67%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.89 (1H, t), 7.35 (2H, t), 7.10 (1H, t), 7.09 (2H, d), 6.96 (1H, d), 6.91 (1H, d ), 6.46 (1H, s), 4.84 (1H, s), 4.32~4.27 (1H, m), 3.87 (1H, s), 3.78 (1H, s), 3.53 (1H, s), 3.43 (2H, d), 3.19 (2H, d), 2.72 (1H, t), 2.52 (1H, d), 2.28 to 2.19 (1H, m), 2.10 to 1.94 (4H, m), 1.92 to 1.84 (1H, m) , 1.78 (2H, s), 1.70~1.48 (4H, m), 0.92 (3H, t)

Example 131: 4-{4-[2-Fluoro-4-(2-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester from Preparation Example 70 (70 mg, 0.16 mmol Reaction with propylamine in the same manner as in Example 1 to give the title compound (62 mg, yield 74%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.35 (2H, t), 7.19 (1H, t), 7.16~7.11 (1H, m), 7.10 (2H, d), 7.03 (1H, d), 6.95~6.84 (1H, m), 6.70 (1H, d), 4.91 (1H, s), 4.32~4.27 (1H, m), 3.87 (1H, s), 3.76 (1H, s), 3.54 (1H, s), 3.44(2H,d), 3.15(2H,s), 3.04(1H,t),2.52(1H,d), 2.30~2.22(1H,m), 2.10~1.95(4H,m),1.93~1.85( 1H,m), 1.79(2H,s), 1.70~1.44(4H,m),0.91(3H,t)

Example 132: 4-(4-{3-Fluoro-4-[3-(2-hydroxy-ethyl)-ureido]- Phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester of Preparation 71 (70 mg, 0.16 mmol) Reaction with 2-amino-1-ethanol in the same manner as in Example 1 gave the title compound (45 mg, yield 53%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.85 (1H, t), 7.35 (2H, t), 7.19 (1H, t), 7.11 (2H, d), 6.97 (1H, d), 6.91 (1H, d ), 6.79 (1H, d), 5.34 (1H, s), 4.32~4.27 (1H, m), 3.87 (1H, s), 3.80~3.70 (3H, m), 3.53 (1H, s), 3.47~ 3.35(4H,m), 2.78~2.62(2H,m),2.53(1H,d), 2.28~2.19(1H,m), 2.10~1.94(4H,m),1.92~1.84(1H,m), 1.78(2H,s), 1.68~1.50(2H,m)

Example 133: 4-(4-{2-Fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneamino)-piperidine-1-carboxylate Acid phenyl ester

4-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneamino]-piperidine-1-carboxylic acid phenyl ester from Preparation Example 70 (70 mg, 0.16 mmol) )versus 2-Amino-1-ethanol was reacted in the same manner as in Example 1 to give the title compound (39 mg, yield 46%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.35 (2H, t), 7.20 (1H, t), 7.18 to 7.11 (1H, m), 7.10 to 7.03 (3H, m), 6.95 to 6.86 (1H, m) , 6.85 (1H, d), 5.22 (1H, s), 4.32~4.27 (1H, m), 3.87 (1H, s), 3.82~3.70 (3H, m), 3.54 (1H, s), 3.48~3.34 (4H,m), 3.05(1H,t), 2.73(1H,d),2.53(1H,d), 2.30~2.22(1H,m),2.09~1.96(4H,m),1.93~1.85(1H , m), 1.79 (2H, s), 1.71~1.52 (2H, m)

Example 134: 4-{4-[4-(3,3-Dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester

3-[2-Fluoro-4-(4-oxocyclohexyl)phenyl]-1,1-dimethylurea (0.018 g, 0.06 mmol) from Preparation 63 and 4-aminooxy The phenylpiperidine-1-carboxylic acid phenyl ester (0.015 g, 0.06 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.01 (1H, t), 7.36 (2H, t), 7.18 (1H, t), 7.10 (2H, d), 6.92 (2H, m), 6.50 (1H, m ), 4.29 (1H, m), 3.80 (2H, m), 3.51 (1H, m), 3.42 (2H, m), 3.04 (6H, s), 2.72 (1H, m), 2.50 (1H, m) , 2.24 (1H, m), 2.06 (4H, m), 1.88 (1H, m), 1.80 (2H, m), 1.63 (2H, m)

Example 135: 4-(4-{3-Fluoro-4-[3-(2-fluoro-ethyl)-ureido]-benzene Benzyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid phenyl ester (0.049 g, 0.11 mmol) and 2-fluoroethyl The amide hydrochloride was reacted in the same manner as in Example 1 to give the title compound (0.04 g, yield 67%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.83 (1H, t), 7.35 (2H, t), 7.19 (1H, t), 7.11 (2H, m), 6.97 (1H, m), 6.93 (1H, m ), 6.30 (1H, m), 4.98 (1H, m), 4.59 (2H, t), 4.50 (2H, t), 4.23 (1H, m), 3.85 (2H, m), 3.63 (1H, m) , 3.57 (1H, m), 3.55 (1H, m), 3.43 (2H, m), 2.74 (1H, m), 2.53 (1H, m), 2.25 (1H, m), 2.04 (4H, m), 1.89 (1H, m), 1.80 (2H, m), 1.65 (2H, m)

Example 136: 3-(2-Fluoro-4-{4-[1-(3,3,3-trifluoro-propyl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl )-1,1-dimethyl-urea

4-({4-[4-(Dimethylaminocarbamimidino)-3-fluorophenyl]cyclohexylene}amino)-oxypiperidine-1-carboxylate from Preparation 64 The acid tert-butyl ester (0.05 g, 0.1 mmol) was cooled to 0 ° C and 4N HCl/1,4-di was added. The alkane (3 mL) was stirred at room temperature for 2 h. The reaction mixture was distilled under reduced pressure and dried under reduced pressure. After adding dichloroethane (1 mL) to the above unpurified reaction mixture, 3,3,3-trifluoropropanal (0.013 g, 0.1 mmol) and sodium triethoxypropoxyborohydride (0.033 g, 0.15) were added. Mm). A small amount of acetic acid was added dropwise to the reaction mixture, the pH was adjusted to 5, and stirred at room temperature. The TLC confirmation reaction was completed. A 1 N sodium hydroxide solution was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO.

NMR: ¹ H-NMR (CDCl ₃ ) 8.00 (1H, t), 6.94 (1H, m), 6.89 (1H, m), 6.46 (1H, m), 4.07 (1H, m), 3.39 (1H, m ), 3.03 (6H, s), 2.70 (3H, m), 2.59 (2H, m), 2.48 (1H, m), 2.30 (4H, m), 2.21 (1H, m), 2.02 (4H, m) , 1.85 (1H, m), 1.72 (2H, m), 1.58 (2H, m)

Example 137: 3-{4-[4-(1-Benzyl-piperidin-4-yloxyimino)-cyclohexyl]-2-fluoro-phenyl}-1,1-dimethyl- Urea

4-({4-[4-(Dimethylaminocarbamimidino)-3-fluorophenyl]cyclohexylene}amino)-oxypiperidine-1-carboxylate from Preparation 64 The acid tert-butyl ester (0.05 g, 0.1 mmol) was obtained from the title compound (yield: 61%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.00 (1H, t), 7.32 (5H, m), 6.94 (1H, m), 6.87 (1H, m), 6.46 (1H, m), 4.11 (1H, m) ), 3.61 (2H, s), 3.36 (1H, m), 3.03 (6H, s), 2.72 (3H, m), 2.48 (1H, m), 2.35 (1H, m), 2.20 (1H, m) , 2.02 (5H, m), 1.83 (3H, m), 1.58 (2H, m)

Example 138: 3-{2-Fluoro-4-[4-(1-naphthalen-2-ylmethyl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-1,1- Dimethyl-urea

4-({4-[4-(Dimethylaminocarbamimidino)-3-fluorophenyl]cyclohexylene}amino)-oxypiperidine-1-carboxylate from Preparation 64 The acid tert-butyl ester (0.05 g, 0.1 mmol) was reacted in the same manner as Example 136 to give the title compound (0.023 g, yield 42%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.00 (1H, t), 7.83 (3H, m), 7.76 (1H, m), 7.51 (1H, m), 7.46 (2H, m), 6.95 (1H, m ), 6.89 (1H, m), 6.48 (1H, m), 4.13 (1H, m), 3.72 (2H, s), 3.38 (1H, m), 3.04 (6H, s), 2.73 (2H, m) , 2.48 (1H, m), 2.37 (1H, m), 2.20 (1H, m), 2.00 (4H, m), 1.83 (2H, m), 1.60 (2H, m), 1.26 (3H, m)

Example 139: 4-(4-{3-Fluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexylideneamino)-peripipeline Phenyl-1-carboxylate

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid phenyl ester (0.039 g, 0.09 mmol) and 3-hydroxy nitrogen The heterocyclic butane hydrochloride salt was reacted in the same manner as in Example 1 to give the title compound (0.031 g, yield: 64%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.00 (1H, t), 7.35 (2H, t), 7.19 (1H, t), 7.11 (2H, d), 6.95 (1H, m), 6.90 (1H, m ), 6.10 (1H, m), 4.65 (1H, m), 4.29 (3H, m), 3.93 (2H, m), 3.86 (1H, m), 3.77 (1H, m), 3.54 (1H, m) , 3.42 (2H, m), 2.73 (2H, m), 2.53 (1H, m), 2.23 (1H, m), 2.00 (4H, m), 1.88 (1H, m), 1.79 (2H, m), 1.60 (2H, m)

Example 140: 4-(4-{3-Fluoro-4-[3-(2-fluoro-ethyl)-ureido]-phenyl}-cyclohexylideneamino)-piperidine-1-carboxylate Isopropyl acrylate

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid isopropyl ester from Preparation 66 (0.06 g, 0.15) The title compound (0.05 g, yield 67%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, m), 6.94 (2H, m), 6.61 (1H, brs), 5.34 (1H, brs), 4.91 (1H, m), 4.57 (1H, m ), 4.48 (1H, m), 4.22 (1H, m), 3.70 (2H, m), 3.61 (1H, m), 3.56 (1H, m), 3.40 (1H, m) 3.28 (2H, m), 2.72 (1H, m), 2.50 (1H, m), 2.22 (1H, m), 2.00 (2H, m), 1.87 (3H, m), 1.60 (4H, m), 1.24 (6H, d)

Example 141: 4-(4-{3-Fluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneamino)-piperidine-1-carboxylate Isopropyl acrylate

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid isopropyl ester from Preparation 66 (0.06 g, 0.15) The title compound (0.04 g, yield 54%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.84 (1H, t), 6.95 (1H, m), 6.93 (1H, m), 6.57 (1H, m), 5.19 (1H, m), 4.92 (1H, m ), 4.48 (1H, t), 4.22 (1H, m), 3.79 (2H, m), 3.70 (2H, m), 3.65 (1H, t), 3.45 (2H, m), 3.40 (1H, m) , 3.28 (1H, m), 2.72 (1H, m), 2.50 (2H, m), 2.23 (1H, m), 2.05 (1H, m), 2.01 (1H, m), 3.87 (3H, m), 1.64 (2H, m), 1.25 (6H, d)

Example 142: 3-{4-[2-Fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-pyrrolidine-1-carboxylic acid phenyl ester

1-Chloro-2-fluoro-4-nitro-benzene was reacted in the same manner as in Preparations 1, 2 and 3 to synthesize 4-(4-amino-2-fluorophenyl)-cyclohexanone. 3-Aminooxy-pyrrolidine-1-carboxylic acid phenyl obtained by the reaction of 3-hydroxy-pyrrolidin-1-carboxylic acid tert-butyl ester according to the methods of Preparations 14, 32 and 15 The ester was used in the same manner as in Preparation 5 to prepare 3-[4-(4-amino-2-fluoro-phenyl)-cyclohexylideneaminooxy]-pyrrolidine-1-carboxylic acid phenyl. Ester (0.02 g, 0.05 mmol). The compound which was synthesized was reacted in the same manner as in Example 1 to give the title compound (0.008 g, yield 30%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.53 (2H, m), 7.25 - 7.00 (4H, m), 7.00 (1H, m), 6.88 (1H, m), 6.60 (1H, m), 4.88 (2H) , m), 3.90~3.50(4H,m), 3.41~3.40(1H,m), 3.10(2H,m), 3.00(1H,m), 2.49(1H,m),2.35~2.22(2H,m ), 2.10~1.80(3H,m), 1.80(1H,m), 1.70~1.46(4H,m),0.95(3H,m)

Example 143: 4-(4-{3-Fluoro-4-[3-(2-hydroxy-1-methyl-ethyl)-ureido]-phenyl}-cyclohexyleneaminooxy)-peripipeline Isopropyl 1-carboxylic acid ester

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid isopropyl ester from Preparation 66 (0.1 g, 0.25) The title compound (0.065 g, yield 51%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.88 (1H, t), 7.06 (1H, s), 6.93 (1H, m), 6.87 (1H, m), 5.35 (1H, d), 4.90 (1H, m ), 4.22 (1H, m), 3.97 (1H, m), 3.70 (3H, m), 3.52 (1H, m), 3.37 (1H, m), 3.28 (2H, m), 3.16 (1H, m) , 2.71 (1H, m), 2.48 (1H, m), 2.22 (1H, m), 2.00 (2H, m), 1.91 (3H, m), 1.54 (4H, m), 1.25 (6H, d), 1.16(3H,d)

Example 144: 4-(4-{3-Fluoro-4-[3-(2-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneamino)-piperidine-1-carboxylate Isopropyl acrylate

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid isopropyl ester from Preparation 66 (0.1 g, 0.25) The title compound (0.11 g, yield 87%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.84 (1H, t), 6.95 (1H, m), 6.92 (1H, m), 6.58 (1H, brs), 5.12 (1H, m), 4.91 (1H, m ), 4.22 (1H, m), 3.98 (1H, m), 3.72 (2H, m), 3.42 (2H, m), 3.27 (2H, m), 3.13 (1H, m), 2.72 (1H, m) , 2.50 (1H, m), 2.43 (1H, m), 2.23 (1H, m), 2.05 (2H, m), 1.85 (3H, m), 1.63 (3H, m), 1.25 (6H, d), 1.22(3H,d)

Example 145: 4-(4-{3-Fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylate Isopropyl acrylate

4-{[4-(4-Amino-3-fluorophenyl)cyclohexylene]amino}oxypiperidine-1-carboxylic acid isopropyl ester from Preparation 66 (0.1 g, 0.25) The title compound (0.042 g, yield 33%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.84 (1H, t), 6.95 (1H, m), 6.92 (1H, m), 6.63 (1H, brs), 5.28 (1H, m), 4.91 (1H, m ), 4.22 (1H, m), 3.70 (4H, m), 3.43 (3H, m), 3.28 (2H, m), 3.13 (1H, brs), 2.72 (1H, m), 2.51 (1H, m) , 2.23 (1H, m), 2.01 (2H, m), 1.86 (3H, m), 1.72 (2H, m), 1.62 (3H, m), 1.54 (1H, m), 1.25 (6H, d)

Example 146: 4-{4-[3-Fluoro-4-(3-methyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.1 g, obtained from Preparation 59) The title compound (0.078 g, yield 68%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.85 (1H, t), 6.94 (1H, m), 6.92 (1H, m), 6.20 (1H, s), 4.91 (1H, m), 4.55 (1H, m) ), 4.22 (1H, m), 3.70 (2H, m), 3.43 (1H, m), 3.26 (2H, m), 2.86 (3H, d), 2.72 (1H, m), 2.51 (1H, m) , 2.22 (1H, m), 2.01 (2H, m), 1.86 (3H, m), 1.62 (3H, m), 1.54 (1H, m), 1.22 (6H, d)

Example 147: 4-{4-[3-Fluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.1 g, obtained from Preparation 59) The title compound (0.129 g, yield 99%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.88 (1H, t), 6.94 (1H, m), 6.92 (1H, m), 6.18 (1H, s), 4.91 (1H, m), 4.42 (1H, m ), 4.22 (1H, m), 4.00 (1H, m), 3.70 (2H, m), 3.42 (1H, m), 3.26 (2H, m), 2.72 (1H, m), 2.51 (1H, m) , 2.22 (1H, m), 2.01 (2H, m), 1.86 (3H, m), 1.62 (3H, m), 1.54 (1H, m), 1.25 (6H, d), 1.22 (6H, d)

Example 148: 4-{4-[4-(3,3-Dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidinyl-carboxylic acid isopropyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.1 g, obtained from Preparation 59) The title compound (0.113 g, yield 95%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.01 (1H, t), 6.94 (1H, m), 6.92 (1H, m), 6.47 (1H, s), 4.91 (1H, m), 4.22 (1H, m) ), 3.70 (2H, m), 3.42 (1H, m), 3.26 (2H, m), 3.00 (6H, s), 2.72 (1H, m), 2.51 (1H, m), 2.22 (1H, m) , 2.07(2H,m), 1.86(3H,m),1.62(3H,m),1.54(1H,m),1.23(6H,d)

Example 149: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl) -methyl-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 47 ]-肟(47 mg, 0.11 mmol), 2.0 M methylamine in tetrahydrofuran (0.5 mL, 1.0 mmol), diisopropylethylamine (70 mg, 0.54 mmol) and triphosgene (35 mg, 0.12 mmol) The title compound (42 mg, yield 78%) was obtained.

^{1 H-NMR (400MHz, DMSO} ): δ 8.26 (s, 2H), 8.19 (1H, s), 7.97 (t, 1H), 7.08 (d, 1H), 6.98 (d, 1H), 6.40 (m, 1H), 4.24 (m, 1H), 4.12 (m, 2H), 3.44 (m, 2H), 3.26 (m, 1H), 2.72 (m, 1H), 2.65 (d, 3H), 2.41 (m, 3H) ), 2.26 (td, 1H), 1.92 (m, 5H), 1.51 (m, 4H), 1.14 (m, 3H)

Example 150: 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl) -3-(2-hydro-1-methyl-ethyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl obtained from Preparation 47 ]-肟(47 mg, 0.11 mmol), 2-amino-propan-1-ol (70 mg, 0.93 mmol), diisopropylethylamine (70 mg, 0.54 mmol) and triphosgene (35 mg, 0.12 mmol) The title compound (51 mg, yield 87%) was obtained.

^{1 H-NMR (400MHz, DMSO} ): δ 8.26 (s, 2H), 8.19 (1H, s), 7.80 (t, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 6.54 (d, 1H), 4.79 (m, t), 4.24 (m, 1H), 4.12 (m, 2H), 3.43 (m, 4H), 3.26 (m, 1H), 2.72 (m, 1H), 2.41 (m, 3H) ), 2.25 (td, 1H), 1.91 (m, 5H), 1.55 (m, 4H), 1.14 (m, 3H), 1.07 (d, 3H)

Example 151: 4-{4-[3-Fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidinyl-carboxylic acid isopropyl ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.1 g, obtained from Preparation 59) The title compound (0.111 g, yield 91%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.87 (1H, t), 6.96 (1H, m), 6.91 (1H, m), 6.22 (1H, s), 4.92 (1H, m), 4.42 (1H, m ), 4.22 (1H, m), 3.70 (2H, m), 3.42 (1H, m), 3.32~3.18 (4H, m), 2.72 (1H, m), 2.51 (1H, m), 2.22 (1H, m), 2.01 (2H, m), 1.86 (3H, m), 1.62 (3H, m), 1.54 (6H, m), 1.25 (6H, d), 1.22 (6H, d)

Example 152: 4-(4-{3-Fluoro-4-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-phenyl}-cyclohexyleneaminooxy)-peripipeline Isopropyl 1-carboxylic acid ester

4-[4-(4-Amino-3-fluoro-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester (0.15 g, obtained from Preparation 59) 0.38 mmol) and 2-methylamino-ethanol were reacted in the same manner as in Example 1 to give the title compound (0.11 g, yield: 58%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.91 (1H, t), 7.37 (1H, s), 6.96 (2H, m), 4.93 (1H, m), 4.22 (1H, m), 3.80 (2H, m ), 3.70 (2H, m), 3.60 (2H, m), 3.42 (1H, m), 3.30 (2H, m), 3.02 (3H, s), 2.72 (1H, m), 2.59 (1H, s) , 2.48 (1H, m), 2.22 (1H, m), 2.01 (2H, m), 1.86 (3H, m), 1.62 (3H, m), 1.54 (1H, m), 1.22 (6H, d)

Example 153: 1-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.88 (1H, t), 6.95 (1H, d), 6.91 (1H, d), 6.34 (1H, s), 4.75 (1H, s), 4.32~4.27 (1H) , m), 3.81~3.74(2H,m), 3.54~3.48(2H,m), 3.37(1H,d),3.23(2H,q),2.92~2.83(1H,m),2.72(1H,t ), 2.52 (1H, d), 2.28~2.19 (1H, m), 2.10~1.96 (4H, m), 1.90~1.78 (3H, m), 1.66~1.50 (4H, m), 1.29 (6H, d ), 0.95 (3H, t)

Example 154: 3-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was obtained from the titled compound (18 mg, yield 77%). .

NMR: ¹ H-NMR (CDCl ₃ ) 8.02 (1H, t), 6.95 (1H, d), 6.91 (1H, d), 6.46 (1H, s), 4.32 to 4.27 (1H, m), 3.81 to 3.74 (2H,m), 3.54~3.48(2H,m), 3.40(1H,d),3.04(6H,s),2.92~2.83(1H,m),2.71(1H,t),2.52(1H,d ), 2.28~2.19(1H,m), 2.10~1.96(4H,m), 1.90~1.78(3H,m),1.68~1.50(2H,m),1.29(6H,d)

Example 155: 1-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was reacted with 2-methoxyethylamine to give the title compound (15 mg, yield 60%) ).

NMR: ¹ H-NMR (CDCl ₃ ) 7.92 (1H, t), 6.95 (1H, d), 6.91 (1H, d), 6.86 (1H, s), 5.09 (1H, s), 4.32~4.27 (1H) , m), 3.82~3.75(2H,m), 3.52~3.36(10H,m), 2.92~2.83(1H,m),2.72(1H,t),2.52(1H,d),2.28~2.19(1H , m), 2.10~1.96(4H,m), 1.90~1.78(3H,m), 1.68~1.50(2H,m),1.29(6H,d)

Example 156: 1-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was obtained from the title compound (17 mg, yield 71%).

NMR: ¹ H-NMR (CDCl ₃ ) 7.89 (1H, t), 6.95 (1H, d), 6.90 (1H, d), 6.31 (1H, s), 4.55 (1H, s), 4.32 to 4.27 (1H) , m), 4.02~3.95(1H,m), 3.81~3.74(2H,m), 3.55~3.48(2H,m), 3.40(1H,d),2.92~2.83(1H,m),2.71(1H , t), 2.52 (1H, d), 2.28~2.19 (1H, m), 2.10~1.96 (4H, m), 1.90~1.78 (3H, m), 1.66~1.50 (2H, m), 1.29 (6H) , d), 1.19 (6H, d)

Example 157: (2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 Diazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) and 0.5 N ammonia The title compound (19 mg, yield 86%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, t), 6.98 (1H, d), 6.93 (1H, d), 6.55 (1H, s), 4.70 (2H, s), 4.32~4.27 (1H) , m), 3.82~3.74(2H,m), 3.55~3.48(2H,m), 3.41(1H,d),2.92~2.83(1H,m),2.73(1H,t),2.52(1H,d ), 2.28~2.19(1H,m), 2.10~1.96(4H,m), 1.90~1.78(3H,m),1.66~1.50(2H,m),1.29(6H,d)

Example 158: 1-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was reacted with 2-amino-propan-1-ol in the same manner as in Example 1 to give the title compound 21 mg (yield 84). %).

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, t), 6.97 (1H, d), 6.92 (1H, d), 6.63 (1H, s), 4.88 (1H, s), 4.32~4.27 (1H) , m), 4.03~3.95(1H,m), 3.81~3.71(3H,m), 3.60~3.48(3H,m),3.41(1H,d),2.92~2.83(1H,m),2.76~2.65 (2H,m), 2.52(1H,d), 2.28~2.19(1H,m), 2.10~1.96(4H,m),1.90~1.78(3H,m),1.66~1.50(2H,m),1.29 (6H,d), 1.20(3H,d)

Example 159: 1-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was obtained from the titled compound (yield: .

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, t), 6.97 (1H, d), 6.92 (1H, d), 6.77 (1H, s), 5.31 (1H, s), 4.32~4.27 (1H) , m), 4.01~3.94(1H,m), 3.82~3.73(2H,m), 3.55~3.48(2H,m), 3.47~3.38(2H,m),3.18~3.10(1H,m),2.92 ~2.83(1H,m), 2.72(1H,t),2.58(1H,s),2.52(1H,d), 2.28~2.19(1H,m),2.10~1.96(4H,m),1.90~1.78 (3H,m), 1.66~1.50(2H,m), 1.28(6H,d),1.21(3H,d)

Example 160: 1-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was obtained from m.

NMR: ¹ H-NMR (CDCl ₃ ) 7.86 (1H, t), 6.95 (1H, d), 6.91 (1H, d), 6.48 (1H, s), 4.87 (1H, s), 4.32~4.27 (1H) , m), 3.82~3.74(2H,m), 3.55~3.48(2H,m), 3.40(1H,d),2.92~2.81(4H,m),2.72(1H,t),2.52(1H,d ), 2.28~2.19 (1H, m), 2.10~1.96 (4H, m), 1.90~1.78 (3H, m), 1.66~1.50 (2H, m), 1.28 (6H, d)

Example 161: 3-Hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4]] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was reacted with 3-hydroxy-azetidine hydrochloride (m. Yield 69%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.03 (1H, t), 6.95 (1H, d), 6.91 (1H, d), 6.09 (1H, s), 4.74~4.70 (1H, m), 4.33~4.27 (3H,m), 3.99~3.94(2H,m),3.81~3.74(2H,m),3.55~3.48(2H,m), 3.40(1H,d),2.92~2.81(1H,m),2.72 (1H, t), 2.52 (1H, d), 2.28~2.19 (2H, m), 2.10~1.96 (4H, m), 1.90~1.78 (3H, m), 1.66~1.50 (2H, m), 1.29 (6H,d)

Example 162: 1-(2-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea

4-(4-Amino-3-fluoro-phenyl)-cyclohexanone O-[1-(3-isopropyl-[1,2,4] from Preparation 72 The oxazol-5-yl)-piperidin-4-yl]-indole (20 mg, 0.05 mmol) was obtained from the title compound (yield: .

NMR: ¹ H-NMR (CDCl ₃ ) 7.84 (1H, t), 6.96 (1H, d), 6.92 (1H, d), 6.46 (1H, s), 5.09 (1H, s), 4.32~4.27 (1H) , m), 3.82~3.69 (4H, m), 3.55~3.38 (5H, m), 3.00 (1H, s), 2.92~2.81 (1H, m), 2.72 (1H, t), 2.52 (1H, d ), 2.28~2.19(1H,m), 2.10~1.96(4H,m), 1.90~1.78(3H,m),1.73~1.68(2H,m),1.66~1.50(2H,m),1.28(6H , d)

Example 163: 1-(6-{4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-pyrimidin-3-yl)- 3-propyl-urea

2-Bromo-5-nitro-pyrimidine (0.11 g, 0.58 mmol) was reacted in the same manner as in Preparations 1, 2, 3 and 7 to give 4-(5-amino-pyridin-2-yl)- Cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole. The title compound (8 mg, yield: 64%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.29 (1H, m), 8.15 (2H, s), 7.92 (1H, m), 7.12 (1H, m), 6.76 (1H, s), 4.94 (1H, m ), 4.30 (1H, m), 4.15 (2H, m), 3.51 (2H, m), 3.40 (1H, m), 3.20 (2H, m), 2.90 (1H, m), 2.50 (1H, m) , 2.26 (1H, m), 2.11 (3H, s), 2.08~1.95 (3H, m), 1.90~1.80 (3H, m), 1.78~1.60 (2H, m), 1.50 (2H, m), 1.40 (2H,m), 0.90(3H,t)

Example 164: 3-[4-(2-Fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzene Base ester

3-[4-(4-Amino-2-fluoro-phenyl)-cyclohexylideneamino]-8-aza-bicyclo[3.2.1]octane-8 from Preparation 74 - carboxylic acid phenyl ester (30 mg, 0.07 mmol) and 0.5 M ammonia The title compound (25 mg, yield 76%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.19 (1H, s), 7.37 (3H, m), 7.14 (4H, m), 6.07 (1H, s), 4.44 (2H, s), 4.35 (1H, s ), 3.84 (2H, s), 3.37 (1H, d), 3.07 (1H, t), 2.55 (1H, d), 2.30~1.90 (12H, m), 1.71 (2H, m)

Example 165: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-((R)-2-hydroxy-1-methyl-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl-indole (0.50 g, 1.2 mmol) and D-aminopropanol (0.18 g, 2.4 mmol)

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.84 (1H, m), 6.93 (1H, s), 6.85 (1H, m), 5.05 (1H, d), 4.30 (1H, m ), 4.13 (2H, m), 3.97 (1H, m), 3.74 (1H, d), 3.53 (3H, m), 3.43 (1H, d), 3.03 (1H, t), 2.68 (1H, s) , 2.53 (1H, d), 2.27 (1H, m), 2.10 (3H, s), 1.98 (4H, m), 1.87 (1H, m), 1.66 (4H, m), 1.22 (3H, d )

Example 166: 1-(2,5-Difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-((S)-2-hydroxy-1-methyl-ethyl)-urea

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-Alkyl-indole (0.50 g, 1.2 mmol) and L-Aminopropanol (0.18 g, 2.4 mmol).

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.84 (1H, m), 6.85 (1H, m), 6.76 (1H, s), 4.86 (1H, d), 4.30 (1H, m ), 4.13 (2H, m), 3.97 (1H, m), 3.75 (1H, d), 3.53 (3H, m), 3.43 (1H, d), 3.03 (1H, t), 2.53 (1H, d) , 2.47 (1H, s), 2.27 (1H, m), 2.10 (3H, s), 1.98 (4H, m), 1.87 (1H, m), 1.66 (4H, m), 1.22 (3H, d)

Example 167: 4-[4-(2,5-Difluoro-4-ureido-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester

4-[4-(4-Amino-2,5-difluoro-phenyl)-cyclohexylideneaminomethyl]-piperidine-1-carboxylic acid tert-butylate from Preparation 76 Base ester (0.05g, 0.11mmol) and 0.5M ammonia The title compound (0.01 g, yield 26%) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 7.87 (1H, m), 6.88 (1H, m), 5.55 (1H, s), 4.63 (2H, s), 4.10 (2H, m), 3.90 (2H, d ), 3.41~3.40(1H,m), 3.00(1H,m), 2.80(2H,m), 2.49~2.46(2H,m),2.35~2.22(1H,m),2.00~1.80(6H,m ), 1.70~1.58(1H,m), 1.46(9H,s), 1.45~1.43(2H,m)

Example 168: 4-(2,5-Difluoro-4-tetrazol-1-yl-phenyl)-cyclohexenone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine -4-yl]-肟

4-(4-Amino-2,5-difluoro-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine obtained from Preparation Example 7 4-yl]-indole (0.11 g, 0.27 mmol) was dissolved in anhydrous acetic acid (0.3 mL), and sodium azide (54 mg, 0.83 mmol) and trimethoxymethane (88 mg, 0.83 mmol) were added sequentially. The mixture was stirred at temperature for 15 minutes. Further, the mixture was further stirred at 80 ° C for 1 hour. The reaction mixture was distilled under reduced pressure and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium

NMR: ¹ H-NMR (CDCl ₃ ) 9.11 (1H, m), 8.16 (2H, s), 7.72 (1H, m), 7.24 (1H, m), 4.33 (1H, m), 3.53~3.47 (3H) , m), 3.20 (2H, t), 2.59 (2H, t), 2.30 (1H, t), 2.10 (3H, s), 2.03 to 1.97 (5H, m), 1.77 to 1.64 (2H, m)

Example 169: 4-p-tolyl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

1-Bromo-4-methyl-benzene (0.08 g, 0.59 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.15 (2H, s), 7.10 (4H, m), 4.19 to 4.10 (3H, m), 3.52 to 3.45 (3H, m), 2.80 (1H, m), 2.67 ~2.57(1H,m), 2.31(3H,s), 2.20(2H,m),2.11(3H,s),2.05~1.95(2H,m),1.85~1.60(4H,m),1.36(3H , t)

Example 170: 4-Naphthyl-2-yl-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-oxime

2-Bromo-naphthalene (0.12 g, 0.59 mmol) was obtained.

NMR: ¹ H-NMR (CDCl ₃ ) 8.16 (2H, s), 7.80 (3H, m), 7.64 (1H, m), 7.50 to 7.30 (3H, m), 4.33 (1H, m), 4.18 (2H) , m), 3.52~3.45(3H,m), 2.94(1H,m), 2.60(1H,m), 2.32(1H,m),2.11(3H,s),2.05~1.95(2H,m), 1.85~1.60(2H,m), 1.36(3H,t)

Example 171: 3-Hydroxy-azetidine-1-carboxylic acid (3-methyl-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl) Oxyimido]-cyclohexyl}-phenyl)-guanamine

1-Bromo-2-methyl-4-nitro-benzene (0.12 g, 0.57 mmol) was reacted in the same manner as in Preparations 1, 2, 3 and 7 to give 4-(4-amino-2- Methyl-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl] - Hey. This compound was reacted with 3-hydroxy-azetidine hydrochloride in the same manner as in Example 1 to give the title compound (15 mg, yield: 85%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.19 to 7.06 (3H, m), 5.87 (1H, s), 4.67 (1H, m), 4.31 to 4.20 (3H, m), 4.15 (2H, m), 3.90 (2H, m), 3.52~3.45 (3H, m), 2.90 (1H, m), 2.55 (1H, m), 2.32 (3H, s), 2.20~2.20 (1H, m ), 2.11 (3H, s), 2.08~1.95 (3H, m), 1.90~1.80 (1H, m), 1.78~1.60 (2H, m), 1.50~1.40 (2H, m)

Example 172: 3-Hydroxy-azetidine-1-carboxylic acid (3-methoxy-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4- Methoxyimino]-cyclohexyl}-phenyl)-guanamine

1-Chloro-2-methoxy-4-nitro-benzene (0.10 g, 0.57 mmol) was reacted in the same manner as in Preparations 1, 2, 3 and 7 to give 4-(4-amino-2). -Methoxy-phenyl)-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole. The compound was reacted with 3-hydroxy-azetidine hydrochloride in the same manner as in Example 1 to give the title compound (8mg, yield: 64%).

NMR: ¹ H-NMR (CDCl ₃ ) 8.14 (2H, s), 7.28 (1H, m), 7.0 (1H, m), 6.65 (1H, m), 5.92 (1H, s), 4.76 (1H, m ), 4.28 (3H, m), 4.15 (2H, m), 3.92 (2H, m), 3.82 (3H, s), 3.51 (2H, m), 3.40 (1H, m), 3.12 (1H, m) , 2.50 (1H, m), 2.26 (1H, m), 2.11 (3H, s), 2.08~1.95 (3H, m), 1.90~ 1.80 (1H, m), 1.78~1.60 (2H, m), 1.50 ~1.40(2H,m)

Experimental Example 1: Determination of GPR agonist activity (cell-based assay)

HEK293 hGPR119-luciferase cells were dispensed into each well of a 96-well assay plate (3 x 10 ⁴ cells/90 μl/well), and then cultured in a 5% CO ₂ incubator at 37 ° C for 18 hours. 10 μl of serially diluted GPR119 agonist was added to a final concentration of 1% DMSO, and the cells were cultured in a 5% CO ₂ incubator at 37 ° C for 5 hours. Add 50 μl Bright-Glo ^TM after receiving quality luciferase (Promega), the luminance was measured using a luminometer (Molecular Devices).

The relative percentage (%) of the increased luminosity of the serially diluted agonist was calculated based on the luminosity represented by treatment with only 1% DMSO. EC ₅₀ refers to the concentration of agonist when the luminosity is increased to 50% of the highest value when treated with an agonist. The calculation of this assay was performed using statistical software (Prizm).

By measurement of compound of the above-described Experimental Example Effect receptor agonists shown in Table 1, expressed in units EC ₅₀ (μM). The activity is expressed according to the following criteria: A = 100-20 μM, B = 20-2 μM, C = 2-0.2 μM, D = 0.2-0.01 μM

Claims (12)

An anthraquinone derivative of the formula 1 or a pharmaceutically acceptable salt thereof or an isomer thereof: Wherein RA represents a partially or fully saturated 4- to 7-membered cycloalkyl group, RB represents a partially or fully saturated 4- to 7-membered heterocyclic ring, or consists of two rings [5.5], [5.6], [5.7], [6.6] or [6.7] fused ring system, R1 and R2 each independently represent hydrogen, halogen or alkyl, wherein n represents an integer from 0 to 10, A represents nitrogen or carbon, and B is selected from The following groups: Wherein D represents carbon, nitrogen, oxygen or sulfur, and R3, R4 and R5 are each independently hydrogen or halogen, or respectively represent an aryl group, an arylalkyl group, an alkyl group, a cycloalkyl group or a cycloalkyl group which may be optionally substituted. An alkyl group, a heterocyclic group, a heterocyclic alkyl group or an amine, but the limitation is that when D is oxygen or sulfur, neither R3 nor R4 is present, and when D is sulfur, R5 is not an amine, when D When it is nitrogen, R3 is absent. When D is carbon, two groups selected from R3, R4 and R5 are joined together to form a 3- to 7-membered cycloalkyl or heterocyclic ring which may optionally be substituted, or formed. A 5- or 6-membered aryl or heteroaryl group may be optionally substituted, and E, F, G, H and I each independently represent carbon, nitrogen, oxygen or sulfur to form a 6-membered aryl or heteroaryl group, Or forming a 5-membered aryl or heteroaryl group which does not include one of E, F, G, H and I, n represents an integer from 0 to 5, R6 is hydrogen or halogen; or represents Alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl or heteroarylalkyl optionally substituted; or an amine representing a hydroxy group or optionally substituted with 1 or 2 alkyl or aryl groups Where the two substituents of the amine are linked together Form a 3- to 7-membered heterocyclyl group, J on behalf of the optionally substituted C ₁ -C ₄ - alkylene or acyl sulfo, R7 is hydrogen or halogen, or represents optionally substituted the alkyl, cycloalkyl A aryl, heteroaryl or heterocyclic group, and Ar represents an aryl or heteroaryl group which may be optionally substituted. An anthraquinone derivative according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein A is nitrogen. An anthraquinone derivative according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the B group is selected from the group consisting of: Wherein n, R3, R4, R5, R6 and R7 are as defined in the first item of the patent application. An anthracene derivative as described in claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein Ar represents the following formula: Wherein, K, L, M, Q and T each independently represent carbon or nitrogen to form a phenyl or 6-membered heteroaryl group, or when one of K, L, M, Q and T is absent, represents 5- a heteroaryl group in which oxygen, nitrogen or sulfur can be added as a ring atom, n represents an integer from 1 to 5, and R8 is independently hydrogen, halogen, cyano or nitro, respectively, or an alkyl group which may be optionally substituted, A cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, amine, hydroxy, ethynyl or vinyl group, or selected from the group consisting of: Among them, U is selected from the group consisting of carbon, nitrogen, oxygen, phosphorus and sulfur. When U is sulfur or phosphorus, n stands for 1 or 2 respectively. When U is carbon or nitrogen, n stands for 1, when U is oxygen. , n represents 0, R9 represents hydrogen or may be substituted hydroxy, amine, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, and V represents carbon, nitrogen, oxygen or sulfur, R10, R11 And R12 are each independently hydrogen, halogen or aminemethanyl, or represent a hydroxyl, alkyl, amine, cycloalkyl, heterocyclyl, aryl or heteroaryl group which may optionally be substituted, or selected from R10, R11 and Two of R12 may be joined to form a ring, and when V is oxygen or sulfur, R11 is absent. An anthracene derivative as described in claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the Ar is selected from the group consisting of: Wherein n represents an integer from 1 to 5, R8 is a nitro group, or represents a hydroxy, alkyl, ethynyl, amine, heteroaryl or heterocyclic group which may be optionally substituted, or is selected from the group consisting of: Wherein n, R9, R10, R11 and R12 are as defined in item 4 of the scope of the patent application. An anthraquinone derivative according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein RA is selected from the group consisting of: RB is selected from the following groups: Wherein R 1 and R 2 each independently represent hydrogen or C ₁ -C ₆ -alkyl, wherein n in each ring represents an integer from 0 to 9, A represents nitrogen, and B is selected from the group consisting of: Wherein, n represents an integer of 0 to 5, and R3, R4 and R5 are each independently hydrogen or halogen, or represent C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ - ring Alkyl-C ₁ -C ₆ -alkyl, C ₅ -C ₁₀ -aryl, C ₅ -C ₁₀ -aryl-C ₁ -C ₆ -alkyl, heterocyclyl or heterocyclyl-C ₁ - a C ₆ -alkyl group (wherein the heterocyclic group is a hetero atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom or a fully saturated 3- to 10-membered ring); or R 4 and R 5 are bonded to form a C ₃ -C ₁₀ -cycloalkyl group, or a hetero atom containing from 1 to 3 selected from nitrogen, oxygen and sulfur as a part of a ring atom or a fully saturated 3- to 10-membered ring; wherein R3, R4 and R5 are In the definition, each group may be substituted with at least one group selected from the group consisting of halogen, hydroxy, amine, pendant oxy, carboxy, C ₁ -C ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkyl. R6 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₃ -C ₁₀ -cycloalkyl, C ₁ -C ₆ -alkoxy, C ₅ -C ₁₀ -Aryl or di(C ₁ -C ₆ -alkyl)amine, and n represents 0 or 1, R 7 is hydrogen or halogen, or represents C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkane Base, C ₅ -C ₁₀ -aryl, or include 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as a 5- or 6-membered heteroaryl group of the ring atom, wherein the group defined by R7 may be substituted with at least one group selected from the group consisting of halogen, Hydroxyl, amine, pendant oxy, carboxy, C ₁ -C ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkyl, Ar is selected from the group consisting of: Wherein n represents 1 or 2, R8 is nitro or hydroxy-C ₁ -C ₆ -alkyl, or an amine which may be 1- or 2-substituted by a C ₁ -C ₆ -alkylsulfonyl group, if desired, a part or fully saturated 5- or 6-membered heterocyclic group including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and optionally substituted by a pendant oxy group, or 1 to 4 selected from nitrogen and oxygen And a hetero atom of sulfur as a 5- or 6-membered heteroaryl group of the ring atom, or is selected from the group consisting of: Wherein n represents 1 or 2, and R9 represents an amine group, a hydroxyl group, a C ₁ -C ₆ -alkyl group, a C ₁ -C ₆ -alkoxy group, a C ₃ -C ₁₀ -cycloalkyl group, a C ₃ -C ₁₀ - Cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylamine, bis(C ₁ -C ₆ -alkyl)amine, C ₃ -C ₁₀ -cycloalkylamine, C ₅ - a C ₁₀ -arylamine, a C ₅ -C ₁₀ -aryl-C ₁ -C ₆ -alkylamine, a heterocyclic group or a heterocyclic-C ₁ -C ₆ -alkylamine (wherein the heterocyclic group is included 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as part of a ring atom or fully saturated 3- to 10-membered ring), wherein each ring in the definition of R9 may optionally have at least one group selected from the group consisting of Substituting: halogen, hydroxy, amine, pendant oxy, carboxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxycarbonyl, aminecarboxamyl and C ₁ -C ₆ -alkyl, and R10, R11 and R12 each independently represent hydrogen, hydroxy, halogen, aminemethanyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, hydroxy-C ₁ -C ₆ -alkyl, C _1- C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₅ -C ₁₀ -aryl, C ₁ -C ₆ -alkylamine, di(C ₁ -C ₆ -alkyl)amine , C ₃ -C ₁₀ -cycloalkylamine, C ₅ -C ₁₀ -arylamine or C ₅ -C ₁₀ -aryl-C ₁ -C ₆ -alkylamine, or a heterocyclic group or a heterocyclic group -C ₁ -C ₆ -alkyl,heterocyclyl-C ₁ -C ₆ -alkylamine (wherein the heterocyclic group is a part of a ring atom comprising from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur Or fully saturated 3- to 10-membered ring) or heteroarylalkyl (wherein the heteroaryl group includes 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as part of the ring atom or fully saturated 3- to a 4-membered aromatic ring); or two groups selected from the group consisting of R10, R11 and R12 are bonded to form a C ₃ -C ₁₀ -cycloalkyl group, including 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur as a ring atom a 4- to 6-membered heteroaryl group, or a hetero atom containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as a ring atom or a fully saturated 4- to 6-membered heterocyclic group, wherein R10, R11 And in the definition of R12, each group may be substituted with at least one group selected from the group consisting of halogen, hydroxy, amine, pendant oxy, carboxy, azide, C ₃ -C ₁₀ -cycloalkyl, C ₁ - C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyloxy and C ₁ -C ₆ -alkyl. An anthraquinone derivative according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, which is selected from the group consisting of 4-(4-{2,5-difluoro- 4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid tert-butyl ester; 4 -(4-{2,5-difluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexyleneaminooxy)-piperidine 1-carboxylic acid isopropyl ester; 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-) 3-(piperidin-4-yloxyimino)-cyclohexyl}-phenyl)-guanamine; 3-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)- Piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea; 3-hydroxy-azetidin-1-carboxylate Acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)- Guanidine; 4-cyclopropyl-per pipe 1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-guanamine; (4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl --urea; 4-[4-(2,5-difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester; 4 -[4-(2,5-Difluoro-4-hydroxymethyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester; 4-[4-(2 ,5-difluoro-4-methoxycarbonyl-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester; (2,5-difluoro-4-{ 4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 3-(2,5-difluoro- 4-{4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea 4-[4-(2,5-Difluoro-4-{[(3-hydroxy-azetidin-1-carbonyl)-amino]-methyl}-phenyl)-cyclohexyleneamine Isopropyl]-piperidine-1-carboxylic acid isopropyl ester; 4-[4-(2,5-difluoro-4-ureido-phenyl)-cyclohexyleneaminooxy]-piperidine 1-carboxylic acid isopropyl ester; 4-{4-[2,5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexyleneaminooxy}-peripipeline 1-carboxylic acid isopropyl ester; 4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexyleneaminooxy}-peripipeline Isopropyl 1-carboxylic acid; 4-(4-{2,5-difluoro-4-[3-(2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexyleneamine Isopropyl)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{4-[3-(2,3-dihydroxy-propyl)-ureido]-2,5-difluoro -phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-[4-(4-methanesulfonyl-phenyl)-cyclohexylideneaminooxy ]-piperidine-1-carboxylic acid tert-butyl ester; 4-(4-{4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclo ring Benzylaminooxy)-piperidine-1-carboxylic acid tert-butyl ester; 4-(4-{4-[(3-hydroxy-azetidin-1-yl)-amino]-benzene }}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 3-hydroxy-azetidine-1-carboxylic acid (4-{4-[1-(5- Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 3-hydroxy-azetidin-1-carboxylic acid (2, 5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(2,5-difluoro-4-{4-[1-( 3-isopropyl-[1,2,4] (oxadiazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea; (2,5-difluoro-4 -{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5 -methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1,1-dimethyl-ethyl)- Urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-benzene 3-(2-hydroxy-propyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine- 4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5 -methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea; 1-(2,5 -difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2- Hydroxy-1-hydroxymethyl-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4- Methoxyimido]-cyclohexyl}-phenyl)-3-(2,3-dihydroxy-propyl)-urea; N-(2,5-difluoro-4-{4-[1-( 5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}phenyl)-methanesulfonamide; 1-(3-fluoro-4-{4-[1 -(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxyl (3-ethyl-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (3-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2,4 ] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2,5- Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea; N-(2,5- Difluoro-4-{4-[1-(3-isopropyl-[1,2,4] Oxazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-methanesulfonamide; {2,5-difluoro-4-[4-(1-thiazole) -2-yl-piperidin-4-yloxyimino)-cyclohexyl]-phenyl}-urea; {2,5-difluoro-4-[4-(1-thiazol-2-yl-piperidyl) Methyl pyridin-4-yloxyimino)-cyclohexyl]-phenyl}-aminecarboxylate; {4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxy) Amino)-cyclohexyl]-2,5-difluoro-phenyl}-urea; {4-[4-(1-benzothiazol-2-yl-piperidin-4-yloxyimino)- Cyclohexyl]-2,5-difluoro-phenyl}-aminocarboxylic acid methyl ester; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4- Methoxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(4-{4-[1-(5-B -Pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea; -(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)- 3-(3-hydroxy-2,2-dimethyl-propyl)-urea; 1-(2,5-difluoro-4-{4-[1-(3-isopropyl-[1,2 , 4] Azoxa-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-2,2-dimethyl-propyl)-urea; 2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 3-hydroxy-azetidine-1-carboxylic acid (2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxy) Imino]-cyclohexyl}-phenyl)-guanamine; butane-1-sulfonic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidine-4- 4-[4-(2,5-difluoro-4-indolylcarbonyl-phenyl)-cyclohexane Benzylaminooxy]-piperidine-1-carboxylic acid tert-butyl ester; (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy) Amino]-cyclohexyl}-2,5-difluoro-phenyl)-urea; (R)-3-fluoro-pyrrolidine-1-carboxylic acid (4-{4-[1-(5-ethyl) -pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-decylamine; (4-{4-[1-(5- Ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-3-fluoro-phenyl)-urea; (4-{4-[1-(5-chloro-) Pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea; 1-(4-{4-[1-(5- Chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]- Hexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea; 3-hydroxy-azetidine-1-carboxylic acid {2,5-difluoro-4 -[4-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yloxyimino)-cyclohexyl]-phenyl }-decylamine; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-di Fluoro-phenyl)-3-(2-hydroxy-propyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxy Imino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4- [1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-ethoxy-ethyl)-urea ; 1-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl) 3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine- 4-yloxyimino]-cyclohexyl}-phenyl)-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea; {2,5-difluoro-4-[4 -(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yloxyimino)-cyclohexyl]-phenyl}-urea (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl} -phenyl)-urea; (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl} -phenyl)-urea; 1-(2,3-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]- Cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 3-(4-{4-[1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl Oxyimido]-cyclohexyl}-2,5-difluoro-phenyl)-1,1-dimethyl-urea; 3-(2,5-difluoro-4-{4-[1-( 3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea; 3-(2,6-difluoro-4- {4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea; -(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)- 3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4 -yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea; 1-(2,5-difluoro-4-{4-[ 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea; 1-(2,5-di Fluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy- Propyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-propyl-pyrimidin-2-yl)-per Pyridin-4-yloxyimino]-cyclohexyl}-phenyl)-nonylamine 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl) )-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(2,6-difluoro-4-{4- [1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3 -hydroxy-propyl)-urea; 1-(2,6-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino) ]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 4-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy] - piperidine-1-carboxylic acid isopropyl ester; 4-(4-{2-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexyleneamino Oxy)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2-fluoro-phenyl}- Isocyclohexylamino)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{4-[3-(2-ethoxy-ethyl)-ureido]-2,5 -difluoro-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; (4-{4-[1-(5-cyclopropyl-pyrimidin-2-yl) )-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-urea; 1-(4-{4-[1-(5-cyclopropyl-pyrimidine) -2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea; (2,5 -difluoro-4-{4-[4-(3-isopropyl-[1,2,4] (oxazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea; (2,5-difluoro-4-{4-[4-(3-isopropyl-[ 1,2,4] (oxazol-5-yl)-cyclohexyloxyimino]-cyclohexyl}-phenyl)-urea; (2,5-difluoro-4-{4-[1-(5-methyl-pyrimidine- 2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-dicarbodiimide diamine; 1-(2,5-difluoro-4-{4-[1 -(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea; 3-hydroxy- Azetidine-1-carboxylic acid (2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]- Cyclohexyl}-phenyl)-guanamine; 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimine ]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-fluoro-pyrimidine) -2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea; 1-(2,5-difluoro-4-{4-[ 1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 1-( 2,5-Difluoro-4-{4-[1-(5-fluoro-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-thiophene -2-ylmethyl-urea; (2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl} -phenyl)-urea; (2,3-difluoro-4-{4-[1-(5-methyl-pyrimidine-2) -yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (2,3-difluoro-4- {4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine; 1-(2,3-di Fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy- Propyl)-urea; 1-(2-fluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- Phenyl)-3-(3-hydroxy-propyl)-urea; 3-hydroxy-azetidine-1-carboxylic acid (2-fluoro-4-{4-[1-(5-methyl-) Pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(4-{4-[1-(5-ethyl-pyrimidine-2) -yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl)-3-(3-hydroxy-propyl)-urea; 3-hydroxy-aza Cyclobutane-1-carboxylic acid (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3- Difluoro-phenyl)-guanamine; (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2, 3-difluoro-phenyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl} -2,3-difluoro-phenyl)-3-(2-hydroxy-propyl)- ; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,3-difluoro-phenyl -3-propyl-urea 4-[4-(3-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester; (2 ,5-Difluoro-4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea (4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-urea; -(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-3-( 3-hydroxy-propyl)-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}- 2-fluoro-phenyl)-3-(2-hydroxy-propyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (4-{4-[1-(5-ethyl-) Pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)-guanamine; 4-methyl-2-{4-[1-(5- Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2-{4-[1-( 5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-thiazole-5-carboxylic acid (2-fluoro-ethyl)-decylamine; 4-(5 -hydroxymethyl-4-methyl-thiazol-2-yl)-cyclo Ketone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole; 3-hydroxy-azetidine-1-carboxylic acid (2,5-difluoro 4-{4-[1-(5-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine; 4-( 4-{3-Fluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexylideneamino)-piperidine-1-carboxylic acid Isopropyl ester; 1-(2,5-difluoro-4-{4-[1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]- Cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 3-hydroxy-azetidin-1-carboxylic acid (2,5-difluoro-4-{4-[1 -(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine; [(S)-2-((S) 3-fluoro-pyrrolidin-1-yl)-1-(4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclo Benzyl}-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester; 4-{4-[(S)-2-amino-3-((S)-3- Fluoropyrrolidin-1-yl)-3-oxo-propyl]-phenyl}-cyclohexanone O-[1-(5-methyl-pyrimidin-2-yl)-piperidine-4- 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-di Fluoro-phenyl)-3-methyl-urea; 1-(2,5-difluoro-4-{4-[ 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea; 1-(4-{4- [1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2,5-difluoro-phenyl)-3-isopropyl-urea ; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl -3-isopropyl-urea; 4-[4-(2-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid benzene Base ester; 4-[4-(3-fluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester; 4-[4 -(2,5-difluoro-4-phenoxycarbonylamino-phenyl)-cyclohexylideneaminooxy]-piperidine-1-carboxylic acid phenyl ester; 4-{4-[2, 5-difluoro-4-(3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-{4-[4-( 3,3-Dimethyl-ureido)-2,5-difluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-(4-{2 , 5-difluoro-4-[(3-hydroxy-azetidin-1-carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid benzene Base ester; 4-{4-[2,5-difluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}- Phenylpyridine-1-carboxylate; 3-hydroxy-azetidin-1-carboxylic acid (2,5-difluoro-4-{4-[(Z)-1-(5-methyl) -pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohex-1-enyl}-phenyl)-guanamine; 4-{4-[3-fluoro-4-(3 -propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-{4-[2-fluoro-4-(2-propyl-) Ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl) )-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 4-(4-{2-fluoro-4-[3-(2-hydroxy-) Ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 4-{4-[4-(3,3-dimethyl-urea) Benzyl-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid phenyl ester; 4-(4-{3-fluoro-4-[3-(2-fluoro) -ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 3-(2-fluoro-4-{4-[1-(3 ,3,3-trifluoro-propyl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea; 3-{4-[4- (1-Benzyl-piperidin-4-yloxyimino)-cyclohexyl]-2-fluoro-phenyl}-1,1-dimethyl-urea; 3-{2-fluoro-4- [4-(1-naphthalen-2-ylmethyl-piperidin-4- Oxyimido)-cyclohexyl]-phenyl}-1,1-dimethyl-urea; 4-(4-{3-fluoro-4-[(3-hydroxy-azetidin-1- Carbonyl)-amino]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid phenyl ester; 4-(4-{3-fluoro-4-[3-(2-fluoro) -ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{3-fluoro-4-[3-( 2-hydroxy-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 3-{4-[2-fluoro-4-( 3-propyl-ureido)-phenyl]-cyclohexylideneaminooxy}-pyrrolidine-1-carboxylic acid phenyl ester; 4-(4-{3-fluoro-4-[3-(2) -hydroxy-1-methyl-ethyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{3-fluorine -4-[3-(2-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-(4-{ 3-fluoro-4-[3-(3-hydroxy-propyl)-ureido]-phenyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 4-{ 4-[3-Fluoro-4-(3-methyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester; 4-{4-[ 3-fluoro-4-(3-isopropyl-ureido)-phenyl]-cyclohexylideneaminooxy}-piperidine-1-carboxylic acid isopropyl Ester; 4-{4-[4-(3,3-dimethyl-ureido)-3-fluoro-phenyl]-cyclohexylideneaminooxy}-piperidinyl-carboxylic acid isopropyl ester ; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl)- 1-urea-urea; 1-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-2-fluoro-phenyl --3-(2-hydro-1-methyl-ethyl)-urea; 4-{4-[3-fluoro-4-(3-propyl-ureido)-phenyl]-cyclohexyleneamine Benzyl}-piperidinyl-carboxylic acid isopropyl ester; 4-(4-{3-fluoro-4-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-benzene Isopropyl}-cyclohexylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester; 1-(2-fluoro-4-{4-[1-(3-isopropyl-[1,2 , 4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-propyl-urea; 3-(2-fluoro-4-{4-[1- (3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-1,1-dimethyl-urea; 1-(2-fluoro-4-{4- [1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-methoxy-ethyl)-urea; 1-(2-fluoro- 4-{4-[1-(3-isopropyl-[1,2,4] (oxazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-isopropyl-urea; (2-fluoro-4-{4-[1-( 3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-urea; 1-(2-fluoro-4-{4-[1-(3-isopropyl) Base-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-1-methyl-ethyl)-urea; 1-(2 -fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(2-hydroxy-propyl)-urea; 1-(2-fluoro-4- {4-[1-(3-isopropyl-[1,2,4] Oxazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-methyl-urea; 3-hydroxy-azetidin-1-carboxylic acid ( 2-fluoro-4-{4-[1-(3-isopropyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 1-(2-fluoro-4-{4-[1-(3-iso) Propyl-[1,2,4] Diazol-5-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-(3-hydroxy-propyl)-urea; 1-(2,5-difluoro 4-{4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-3-((R)-2 -hydroxy-1-methyl-ethyl)-urea; 1-(2,5-difluoro-4-{4-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4- Methoxyimino]-cyclohexyl}-phenyl)-3-((S)-2-hydroxy-1-methyl-ethyl)-urea; 4-[4-(2,5-difluoro- 3-ureido-phenyl)-cyclohexylideneaminooxymethyl]-piperidine-1-carboxylic acid tert-butyl ester; 4-(2,5-difluoro-4-tetrazole-1- -Phenyl)-cyclohexenone O-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole; 4-p-tolyl-cyclohexanone O-[ 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yl]-indole; 4-naphthalen-2-yl-cyclohexanone O-[1-(5-methyl-pyrimidine-2 -yl)-piperidin-4-yl]-indole; 3-hydroxy-azetidin-1-carboxylic acid (3-methyl-4-{4-[1-(5-methyl-pyrimidine-) 2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-guanamine; 3-hydroxy-azetidin-1-carboxylic acid (3-methoxy-4) -{4-[1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-cyclohexyl}-phenyl)-decylamine; 1-(6-{4 -[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yloxy And cyclohexyl}-pyrimidin-3-yl)-3-propyl-urea; and 3-[4-(2-fluoro-4-ureido-phenyl)-cyclohexylideneaminooxy]- 8-Aza-bicyclo[3.2.1]octane-8-carboxylic acid phenyl ester. A pharmaceutical composition for use as an agonist of GPR119, which comprises an anthraquinone derivative as described in claim 1 of the patent application, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition for preventing or treating diabetes, diabetic complications, obesity, dyslipidemia or osteoporosis, comprising the anthraquinone derivative according to claim 1 of the patent application, a pharmaceutically acceptable salt thereof or Isomers, and pharmaceutically acceptable carriers. The pharmaceutical composition according to claim 9, wherein the diabetes is type 2 diabetes. A composition for lowering blood glucose concentration, which comprises an anthraquinone derivative as described in claim 1, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier. A method for preparing a composition for preventing or treating diabetes, diabetic complications, obesity, dyslipidemia or osteoporosis, which comprises mixing an anthraquinone derivative as described in claim 1 of the patent application, which is pharmaceutically acceptable a step of a salt or an isomer thereof and a pharmaceutically acceptable carrier.